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Margo Bagley, “De-Materializing Genetic Material: Synthetic Biology and the ABS Bypass”

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Margo Bagley, “De-Materializing Genetic Material: Synthetic Biology and the ABS Bypass”

  1. 1. De-materializing Genetic Resources: Synthetic Biology, Intellectual Property, and the ABS Bypass MARGO A. BAGLEY ASA GRIGGS CANDLER PROFESSOR OF LAW EMORY UNIVERSITY SCHOOL OF LAW
  2. 2. Related Projects •Two Wilson Center Reports •2013 Wilson Center report (with Arti Rai), NP Implementation Issues ◦ Pre-NP legislation ◦ Temporal Scope ◦ Breadth of Coverage •2015 Wilson Center report ◦ Use and Misuse of Digital Information ◦ Synthetic Biology, The Nagoya Protocol, and Intellectual Property Treaties ◦ Possible Future Treaty based ABS/DOO Obligations 2017: UN FAO International Treaty on Plant Genetic Resources for Food and Agriculture (ITPGRFA) report on dematerialization of material in multilateral system
  3. 3. • What is the distinction between synthetic biology and “traditional” genetic engineering? • Many elements are entirely novel • Involves designing and constructing new biological “parts”, “devices” and “systems” • Involves much larger- scale interventions • Pace of change is increasing European Commission Future Brief, Synthetic Biology and biodiversity: http://ec.europa.eu/environment/integration/research/newsalert/pdf/synthetic_biology_biodiver sity_FB15_en.pdf
  4. 4. “Revolutionary” Synthetic Biology “New”chromosome with synthetic nucleotides (new base pair) Could lead to creation of new proteins, cures
  5. 5. Synthetic biology as conservation Pembient (start-up) 3D prints synthetic white rhino horn (modifies DNA of yeast to produce the synthetic keratin) Hopes to flood market, bring down price of real rhino horn ($60,000/kg) so less attractive to poachers “You can’t physically tell the difference. No one looking at this could tell this wasn’t from a rhino. It’s the same thing. For all intents and purposes, this is a real rhino horn.” Matthew Markus, Pembient founder
  6. 6. Vast array of uses Chemical synthesis replacement: Useful to produce high-value chemicals at higher purity and yield than available with traditional chemical synthesis, or more cheaply/greener than conventional synthesis (e.g., vanillin, ginseng, artemesinin, saffron, biofuels, etc.) Gene drives: genetic systems that greatly increase the chances that a genetic alteration will be passed on to an organism’s offspring allowing possibility to change whole populations (e.g. malaria-carrying mosquitos) Biomining: using engineered bacteria to improve efficiency and safety of collecting heavy and precious metals, reduce use of harmful chemicals, cheaper (but risks to natural flora and fauna) Cures for Diseases: new therapeutic products, gene editing; researchers at Stanford used CRISPR/CAS9 to correct sickle cell disease gene National Academies Report on Industrialization of Biology 2015
  7. 7. Total synbio funding (2008-2014) - $580,979,534 Over the past 12 months USD$1 billion invested in synbio companies, led by silicon valley tech investors. Over 410 companies. (Synbiobeta)
  8. 8. Wilson Center “syn bio map” 2013
  9. 9. Synthetic Biology Product Market
  10. 10. www.evolva.com
  11. 11. Community Labs – Science is for EVERYONE
  12. 12. UVA iGEM Team: Nygone 32 billion tons of plastic discarded in U.S. in 2012, 3 billion reclaimed Team engineered a non-pathogenic bacteria to form a biofilm for wastewater filters using parts from registry “we believe that other plastic degrading plasmids from the iGEM registry could be implemented in the same filter. This addition would allow for the optimization of a filter that could degrade all microplastics in the water supply.” http://2014.igem.org/Team:Virginia/Parts
  13. 13. Registries of “standard” biological parts (courtesy of Linda Kahl)
  14. 14. Growing your Own Design Materials https://www.eventbrite.com/e/biotextiles-grow-your-own-materials-for-fashion-design-tickets-32474114952?utm-medium=discovery&utm-campaign=social&utm- content=attendeeshare&utm-source=strongmail&utm-term=listing#
  15. 15. Grow Your Own Design Materials “Today’s biolab is becoming tomorrow’s design studio. Fashion designers have grown materials, garments and accessories from bacteria, yeast, fungi, human bone, synthetic spider silk, and more. In this two-part introduction to biotextiles, you’ll learn how to grow fabrics from microbes and then use natural and bioengineered bacteria to dye them. Our Biotextiles course is a perfect introduction to the latest breakthroughs in fashion and biology and a great way to learn how to start growing your own materials and garments. . . . In the first session, you’ll learn to grow materials and living dyes using microbes. The workshop will be paired with an introduction to biotech in fashion. In the second session, you’ll examine the results and then go over finishing techniques for safe handling of fabrics through sterilization.” https://www.eventbrite.com/e/biotextiles-grow-your-own-materials- for-fashion-design-tickets-32474114952?utm-medium=discovery&utm- campaign=social&utm-content=attendeeshare&utm-source=strongmail&utm-term=listing# .
  16. 16. Synbio and IP: Patents Strong Open-source ethos in synthetic biology, wants free sharing, no patents, but not all SB researchers feel that way Patents: Primary form of IP protection for synbio inventions Some SB inventions that merely copy existing sequences/compounds may not be patent-eligible in U.S., Australia (Myriad Genetics cases), but most should be patent eligible
  17. 17. Patents are Key Form of Protection Marks & Clerk Life Sciences Report 2014
  18. 18. Ethnobiological Research and “Biopiracy” “[t]he patenting of plants, genes, and other biological products that are indigenous to a foreign country without compensating the keepers of those resources and the holders of knowledge appropriated during ethnobiological research processes.” Ex.: Jan. 2016: French Institute agrees to share benefits from Malaria drug patent with French Guianans http://www.sciencemag.org/news/2016/0 2/french-institute-agrees-share-patent- benefits-after-biopiracy-accusations H. Schmidt, mobot.org
  19. 19. Ethnobiological Research and “Biopiracy” Patents may not be involved Ex.:Himalayan seed collection expeditions in 2012-2014, no permission granted for plant removal 60 plant species collected in a single 2014 expedition http://www.bbc.com/news/science- environment-35699297 Zimbabwe 2015: “four live pangolins, toads, two dead pythons, five elephant tusks, three black rhino horns, reptiles, three small tortoises and some unidentified special plant species” taken from national park, found in luggage http://southernafrican.news/2016/01/ 25/bio-piracy-on-the-increase/
  20. 20. Some Researchers Accused of “Biopiracy” Kansas State University professors (patent on gene from Bolivian herbicide- tolerant sorghum seed, licensed to DuPont) Rutgers University professor (patent and applications on pharmaceutical uses of West African kombo butter and Kinkéliba plant extracts) Colorado State University professors (patent on type of hybrid quinoa from Bolivia) Edward Hammond (2013)
  21. 21. Recent “Biopiracy” controversy Ixempra® (a epothilone), BMS developed for breast cancer, +$120 million/yr, derived from South African hyrax soil/dung sample obtained by German researchers
  22. 22. Access and Benefit Sharing: The Convention on Biological Diversity (CBD) Unauthorized utilization and patenting of genetic resources/traditional knowledge - based inventions (“biopiracy”) contributed to creation of the Convention on Biological Diversity (CBD). CBD has 196 Parties, in effect since 1993. Key Principles: ◦ States have sovereign control over biological resources within their borders and shall ensure conservation of same ◦ But states shall endeavor to create conditions to facilitate access on mutually agreed terms and subject to prior informed consent, AND there should be fair and equitable sharing of benefits of use of genetic resources with providing party (PIC/ABS) CBD provides for PIC/ABS but does not specify methodology Parties implemented widely varying legislation (or none at all) to comply Need for uniform framework, enforceable obligations on users, reasonable access provisions by providers
  23. 23. Nagoya Protocol to the CBD: Access and User Compliance Adopted October 2010, came into effect October 2014 Framework for access to genetic resources and traditional knowledge with prior informed consent and on mutually agreed terms, including terms on fair and equitable benefit sharing from utilization of genetic resources and associated traditional knowledge Among other things the Nagoya Protocol: ◦ obligates Parties to designate compliance checkpoints (Art. 17); and ◦ “provide that genetic resources utilized within [their] jurisdiction” have been accessed in accordance with the domestic ABS/PIC/MAT requirements of another Party, and to cooperate in cases where another Party’s domestic ABS legislation has been violated (Art. 15).
  24. 24. Nagoya Protocol Art. 8: Non-commercial Use Smithsonian Institution facilitated inclusion: “In the development and implementation of its access and benefit-sharing legislation or regulatory requirements, each Party shall: ◦ (a) Create conditions to promote and encourage research which contributes to the conservation and sustainable use of biological diversity, particularly in developing countries, including through simplified measures on access for non-commercial research purposes, taking into account the need to address a change of intent for such research”
  25. 25. Non-commercial Bioprospecting Moorea Biocode Project (2006): UC Berkeley et. al., project to collect data (e.g. sequence DNA) on each species on the island ◦ Developed ABS/PIC/MAT agreement with Government of French Polynesia Smithsonian DNA barcode project J. Craig Venter Institute sampling expeditions fewer than 15% of higher plant species are believed to have been examined for bioactivity https://www.aber.ac.uk/en/news/archive/2013/10/title-141883-en.html http://biocode.berkeley.edu/ http://www.ncbi.nlm.nih.gov/genbank/
  26. 26. DNA Sequences as a Screening Tool EPO Opposition filed December 2014 “Members of the coalition of No Patents on Seeds! have filed an opposition against a European patent held by the US company Monsanto. They are accusing Monsanto of biopiracy. The patent EP2134870 was granted in February 2014 by the European Patent Office (EPO) and covers selecting soybean plants adapted to various climate zones for further breeding. For the patent, Monsanto screened more than 250 plants from “exotic” species closely related to the soybean. They were screened specifically for their genetic diversity regarding climate adaptation and the period of time needed to maturity and harvest. The plants were taken from both wild and cultivated species in Asia and Australia. In the patent Monsanto claims the usage of hundreds of DNA sequences originating from natural genetic diversity.” https://www.bernedeclaration.ch/media/press- release/opposition_to_stop_monsanto_soybean_patent_biopiracy/
  27. 27. Digitization (dematerialization) of Genetic Information “Sequencing genomes has now become routine, giving rise to thousands of genomes in the public databases. In essence, scientists are digitizing biology by converting the A, C, T, and G's of the chemical makeup of DNA into 1's and 0's in a computer.” J. Craig Venter Institute
  28. 28. Market Players in Decoupling Design from Synthesis (courtesy of Linda Kahl) Computer-Aided Design (CAD) DNA synthesis and assembly
  29. 29. May be No Need for Tangible Genetic Starting Material “Gene synthesis . . . is like typing the phrase on a word processor. Scientists specify the sequence of the desired gene and have it “printed” at the foundry. They can do this because the complete genome sequences of humans and many other species are available in [online] databases.” Andrew Pollack, New York Times
  30. 30. May be No Need for Tangible Genetic Starting Material “Before the introduction of gene synthesis, Mr. Kuhn had to isolate the genes from the virus itself, then put them into bacteria to have them produce the proteins. Now he orders the genes from DNA2.0, a foundry. “If we were starting this today, I wouldn’t even bother trying to get any of this from the natural source,” Mr. Kuhn said. “I would just order everything.””Andrew Pollack, New York Times
  31. 31. “Digital Biopiracy” “While biopiracy has conventionally meant the physical removal of a material from a community into private hands, synthetic biology enables digital biopiracy, where the DNA of an organism is sequenced in situ, uploaded to the internet as information, and then transferred digitally to a DNA synthesizer so that copies can be rebuilt elsewhere. . . . most synthetic DNA sequences developed for synthetic biology are near-copies of natural genetic code that has ‘evolved’ through computer models.” ETC Group/Friends of the Earth 2010/2012 No need for MTA or PIC/ABS
  32. 32. Similarities/differences to illegal filesharing/downloading of copyrighted material? Revenues from album sales dropped with digital streaming/copying Can expect further reduced ABS revenues as genetic material is digitized Peter Menell
  33. 33. Similarities/differences to illegal filesharing/downloading of copyrighted material (e.g., songs, movies)? Easier and cheaper to copy sequence info and create designer genes now But raw genetic resources not protected by IP by owners (but may be national ABS/PIC/DOO obligations) Harder to detect ownership/improper use (sequences found in multiple species, DNA watermarking/detection expensive, not efficient/not foolproof)
  34. 34. Challenges for ABS
  35. 35. Producing Opiates With Yeast (diverse species inputs) R. Service, Modified Yeast Produces Opiates from Sugar, Science Aug. 2015
  36. 36. Patent Application: Synthetic Biology Substitute for Stevia (Evolva) Synbio production of steviol glocosides in yeast or e. coli involves the use of genes from ~ 30 different possible species including a mushroom, grapevine, legume, and a fungal plant pathogen. Claims to hosts, methods, compositions. Related patent issued from EPO, others pending.
  37. 37. Multiple species may produce the same chain of amino acids
  38. 38. Sequences in Publicly Accessible Databases Pat. App. # US11/38967, US Appl. Pub. # 2013/0171328 Production of Steviol Glycosides in Microorganisms
  39. 39. Scientific Publication (DNA sequence in GENBANK) Production of Sophorolipid from an Identified Current Yeast, Lachancea thermotolerans BBMCZ7FA20, Isolated from Honey Bee CURRENT MICROBIOLOGY Published: AUG 2015 “Biosurfactants are a family of diverse amphipathic molecules that are produced by several microorganisms such as bacteria, molds, and yeasts. These surface active agents have several applications in agriculture, oil processing, food, and pharmaceutical industries. In this research using YMG and YUG culture media, a native yeast strain, HG5, was isolated from honey bee. . . . We named this strain Lachancea thermotolerans strain BBMCZ7FA20 and its 5.8s-rDNA sequence was deposited in GenBank, NCBI under accession number of KM042082.1. . . . In conclusion, this is the first report of sophorolipid production by a native yeast Lachancea thermotolerans BBMCZ7FA20 we isolated from the honey bee gut collected from an apiary farm in Saman, Chaharmahal Bakhtiari province, Iran. . . . According to several applications of biosurfactants in today’s world, the production of sophorolipid by Lachancea thermotolerans could be considered as a potential in the current industrial microbiology and modern microbial biotechnology.”
  40. 40. U.S. Patent Appl. 20140273109A1
  41. 41. Sequences in Publicly Accessible Databases PCT Pub # WO2014082055 A2/ US Pat. App. # US 2014/0162260 A1 Primers, snp markers and method for genotyping mycobacterium tuberculosis
  42. 42. BioBricks Open MTA Goal: Facilitate low transaction costs access to genetic material/information for scientific progress, contractual obligations (open source, but not as good as GNU/Creative Commons copyright-based approaches (e.g., no statutory damages)) Problems: Does not appear to recognize ◦ Benefit sharing obligations of users of material from the MLS ◦ Rights of sovereigns in non-Treaty genetic material/information Appears to view genetic material and informational inputs as common heritage of mankind.
  43. 43. Terms of Transfer UBMTA (1995) Simple Letter (1999) Science Commons (2005-9) OpenMTA (2017) Academia or non-profit only Yes No varies No Use for research and teaching Yes Yes Yes Yes Use for commercial purposes No No varies Yes Distribution of materials or derivatives No No No Yes Fees for preparation and distribution Yes Yes Yes Yes Fees for royalties No No varies No Compliance with laws and regulations Yes Yes Yes Yes Ease of use internationally No Yes varies Yes No warranty (e.g. third party rights) Yes Yes Yes Yes Recipient assumes liability Yes Yes Yes Yes Recipient indemnifies Provider No No varies No Attribution Yes Yes Yes Yes 47 Terms for Transfer of Materials Linda Kahl
  44. 44. The OpenMTA will … 48  Eliminate or reduce transaction costs associated with access, use, modification, and redistribution of materials;  Support collaboration among researchers across institutional and international boundaries;  Promote access to materials for researchers in less privileged institutions and world regions;  Provide an avenue for researchers and their institutions to be credited for materials and data made openly available;  Facilitate translation of biotechnologies into products and services that benefit all people and the planet. Linda Kahl
  45. 45. Does the CBD/Nagoya Protocol and/or ITPGRFA cover intangible genetic information? Unclear. What is clear: Treaties are a floor, not a ceiling
  46. 46. SynBio obligations may come from National Legislation, not Nagoya Protocol Itself Example: Brazil ABS requirements apply to “information of genetic origin from plants, animals, microorganisms or species of other nature, including substances derived from the metabolism of these living beings.” Brazilian Law Nº 13.123, FROM 20 OF MAI 2015
  47. 47. SynBio obligations may come from National Legislation, not Nagoya Protocol Itself Manuela da Silva
  48. 48. Brazilian iGEM team Team isolated a multitrait soybean and maize growth promoting bacterial strain in Brazil from guarana’s rhizophere, wants to engineer it for the competition, it would go into the iGEM registry and be freely accessible (have already published a manuscript on their isolation of the genome sequence)
  49. 49. Create disincentives to access physical material subject to Treaty ITPGRFA Standard Material Transfer Agreement (SMTA) requires sharing of benefits: “6.7 In the case that the Recipient commercializes a Product that is a Plant Genetic Resource for Food and Agriculture and that incorporates Material as referred to in Article 3 of this Agreement, and where such Product is not available without restriction to others for further research and breeding, the Recipient shall pay a fixed percentage of the Sales of the commercialized Product into the mechanism established by the Governing Body for this purpose.” With genetic information (DNA sequences), may not need tangible material anymore, can access sequence, or parts of it, through publicly accessible databases, and obtain value from it.
  50. 50. Create disincentives to access physical material subject to Treaty SMTA limits uses of material from the MLS: “6.1 The Recipient undertakes that the Material shall be used or conserved only for the purposes of research, breeding and training for food and agriculture. Such purposes shall not include chemical, pharmaceutical and/or other non-food/feed industrial uses.” Researchers can use genetic information (DNA sequences) from the Material (obtained through publicly accessible databases) in any kind of research, including chemical and/or pharmaceutical, and obtain value from it.
  51. 51. Conclusions Synthetic biology holds promise for health, food, and quality of life, but also poses challenges for ABS, economic development, and the environment “democratization” of synthetic biology may provide opportunities for low and middle income countries in the global south to advance technologically and develop modified crops, new products and new markets Digital information may create new ways of sharing benefits resulting in more capacity building/technology transfer CBD/NP, FAO ITPGRFA and IGC not clear on how to address the dematerialization of genetic material, in the meantime, national law will govern, but enforcement not always feasible.
  52. 52. Genomic sequencing projects are proceeding; may create disincentives to access material via the Treaty “[The] seed industry enjoys “open access” databases in which crop genomic data is posted and can be accessed without restrictions (or obligations) – yet still be patentable. As synthetic biology develops, the more genomic data that is made available without access and benefit sharing conditions equals more raw materials for corporate patents, entrenching a system that is inherently unfair to small farmers, indigenous peoples and developing countries. . . .” Edward Hammond http://www.pricklyresearch.com/AutoIndex/index.php?dir=DivSeek/

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