Impacts on International Research Collaborations from DSI/ABS Uncertainty

Digital sequence information (DSI) has no clear definition. Numerous countries define DSI as a nonphysical genetic resources, such as genetic sequence data. Restricting free sharing of DSI is at odds with fundamental science core principles in disciplines like microbiology and molecular genetics. It has the potential to adversely affect international research collaborations. Digital sequence information (DSI) has no clear definition. Numerous countries define DSI as a nonphysical genetic resources, such as genetic sequence data. Restricting free sharing of DSI is at odds with fundamental science core principles in disciplines like microbiology and molecular genetics. It has the potential to adversely affect international research collaborations. While technological advancement in the past 20 years has resulted in a proliferation of online genetic resource availability, it has also created increasing international pressure to develop appropriate benefit sharing protocols. The crux of the issue is whether online genetic resource databases constitute traditional knowledge (TK) and, should this be the case, should access and benefits sharing (ABS) be mandatory [1.Smyth S.J. et al.Implications of biological information digitization: access and benefits sharing of plant genetic resources.J. World Intellect. Prop. 2020; 23: 267-287Crossref Scopus (9) Google Scholar]? Historically, international research collaborations have relied on germplasm exchanges facilitated through material transfer agreements; however, access to online genetic resources has greatly reduced the need for physical access to plant and microbial resources. While some nations posit that online digital sequence information (DSI) constitutes TK, other nations with rigorous intellectual property (IP) regimes respond that DSI is simply data, creating global uncertainty for the international plant and microbial research communities [2.Aubry S. The future of digital sequence information for plant genetic resources for food and agriculture.Front. Plant Sci. 2019; 10: 1046Crossref PubMed Scopus (13) Google Scholar]. This article reviews the uncertainties and potential impacts for international research collaborations. Numerous international institutions, including the Convention on Biological Diversity (CBD), the World Intellectual Property Organization, and the International Treaty on Plant Genetic Resources for Food and Agriculture, have invested significant time and effort to provide clarity to this global issue [3.Laird S.A. Wynberg R.P. Fact-Finding and Scoping Study on Digital Sequence Information on Genetic Resources in the Context of the Convention on Biological Diversity and the Nagoya Protocol. Convention on Biological Diversity, 2018Google Scholar]. Virtually all of these efforts have failed, as resolution progress has been glacial, largely due to imprecisely defining DSI (in whether it should be viewed as equivalent to a physical resource) and lack of consideration of the unrestricted sharing of genetic sequence information that is vital to conducting scientific research [4.Karsch-Mizrachi I. et al.The international nucleotide sequence database collaboration.Nucleic Acids Res. 2018; 46: D48-D51Crossref PubMed Scopus (88) Google Scholar]. These efforts at resolution and clarity have been underway for well over a decade, clearly identifying the levels of uncertainty and geo-political pressures that exist. International institutions and treaties are governed through consensus-style decision making, which frequently restricts resolution of challenging, but vitally important, topics and issues. International research partnerships within agriculture are a staple of the efforts to improve global food security. Many partnerships are fostered through the Consortium of International Agricultural Research Centers, public research institutions, and private companies, which are all contributing human and physical resources to this cause. The lack of DSI clarity contributes to the creation of a climate of uncertainty. The traditional requirement of sharing physical and digital data in life sciences does not mean the data does not have value and that benefits should not accrue to jurisdictions in which data originate. On the contrary, contribution to the scientific enterprise and participation in the international scientific community provide benefits to all involved. At present, we are in a global pandemic. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences have been globally shared through the GISAID database in a manner that does not require researchers to relinquish IP and Nextstrain tools [5.Hadfield J. et al.Nextstrain: real-time tracking of pathogen evolution.Bioinformatics. 2018; 34: 4121-4123Crossref PubMed Scopus (689) Google Scholar,6.Deng X. et al.Genomic surveillance reveals multiple introductions of SARS-CoV-2 into Northern California.Science. 2020; 369: 582-587Crossref PubMed Scopus (83) Google Scholar] allow public health bodies to visualize virus movement on a global scale, just as they have been used to share data and facilitate tracking of other diseases, such as influenza and Zika [7.Shu Y. McCauley J. GISAID: global initiative on sharing all influenza data - from vision to reality.Euro Surveill. 2017; 22: 30494Crossref PubMed Scopus (678) Google Scholar]. Data users must acknowledge data contributors and involve them in future research collaborations. There is great potential for similar sequence-based tracking of other plant, animal, and human pathogens that impact our health, livelihood, and economies. The benefits of sequence-based disease tracking for wheat rust diseases (RustTracker.org) or cassava mosaic virus [8.Boykin L. et al.Real time portable genome sequencing for global food security.F1000Res. 2018; 7: 1101Crossref Google Scholar] should be crystal clear. These examples are of obvious practical value in relation to human health and food security. It is important to understand that, even absent this immediate value, sharing DSI has always been required in fundamental life sciences research. Indeed, it would be impossible to restrict access to sequence information that underlies published research. The three main genetic sequence databases that were originally established in the pre-genome sequence era of the 1980s, Genbank, EMBL Nucleotide Sequence Database, and DNA Databank of Japan, share data daily, instantaneously, in an unrestricted manner [9.Gaffney J. et al.Open access to genetic sequence data maximizes value to scientists, farmers, and society.Glob. Food Sec. 2020; 26: 100411Crossref Scopus (6) Google Scholar]. Available to anyone with an internet connection, the open access and immediate nature of these databases is fiercely protected by the scientific community. A decision to permit unrestricted DSI sharing of the data in these databases, or to require cumbersome mutually agreed terms (MAT) negotiations for each instance of access, would make these databases unworkable, ceasing to serve their purpose. Furthermore, MAT negotiations could be extremely challenging in cases where ownership is unclear, disputed, or not claimed. If lack of MAT-enabled databases removes scientists from the scientific conversation, their work would be siloed in obscurity and they would be unable to report research findings or collaborate with fellow scientists. There are existing instances of sharing agreements that have proven successful. Software advances through open-source models are governed on the premise that if programmers contribute to development of specific programs, improvements to them will be shared for the benefit of the community. In agriculture, examples include global seed depositories and Divseek. Establishing a global institution to manage DSI access and the required MAT negotiations is unlikely to succeed, given there has been no global DSI progress, despite a decade of efforts. With global agreement on what constitutes DSI making no progress, it is an even more remote possibility that an international agreement on MAT could be reached. As the consideration of DSI sharing progresses at a sluggish pace, the discipline of synthetic biology advances rapidly, standing the relationship between genetic information and biological material on its end. Researchers can now readily recreate biological material from genetic information sourced from databases, combine genetic information originally sourced from multiple locations, and modify genetic information to produce completely new material different from previously existing material. This capability, along with access to scientific literature, facilitates development of new technologies and applications not beholden to geographic or political borders. Rather than attempting to restrict or otherwise manage access in a manner not completely open, there would be greater benefit in sharing technical knowledge and fostering research collaborations that make use of freely accessible data. The rapidly falling costs of gene synthesis and genome editing are making the creation of value from freely accessible DSI a realistic prospect, regardless of locale. The scientific community does not use the term DSI and yet restriction of DSI sharing is in direct opposition to the fundamentals at the heart of scientific enterprise. There is an obvious tension between the desire to share the benefits from using genetic resources in a fair and equitable way and the foundational requirement that genetic resources be shared for the benefit of all and as an integral component of scientific enterprise. Science is international, ignoring political borders. Restriction of DSI access could have the unintended consequences of isolating researchers from the international scientific community, in effect abolishing their ability to function as scientists. One legitimate, and serious, concern is the potential impacts on international research collaborations (Box 1). Annually, hundreds of millions of US dollars are invested towards the facilitation of North–South research collaborations, designed to increase basic scientific research and the commercialization of innovative products. The mandatory attachment of ABS to DSI, as is being advocated by the CBD and its subsequent subagreement, the Nagoya Protocol, threatens to jeopardize the future of international research collaborations. DSI began to be shared from the early years of DNA sequencing, coordinated through the shared databases of DNA Data Bank of Japan, European Nucleotide Archive, and Genbank [4.Karsch-Mizrachi I. et al.The international nucleotide sequence database collaboration.Nucleic Acids Res. 2018; 46: D48-D51Crossref PubMed Scopus (88) Google Scholar] (Box 2). The research community treats this sequence information as data, not knowledge, and researchers are free to use those data without restrictions. As identified earlier, sharing SARS-CoV-2 sequences is not knowledge, but data that can be used to facilitate knowledge.Box 1International Research CollaborationInternational research collaborations occur regularly, involving every interaction imaginable. Many are ad hoc, resulting from relationships and interactions occurring within international research communities. The following fictional account illustrates how DSI impacts such collaborations.Martha, a graduate student in Alterra, a semi-arid island nation, is developing her thesis research project on plant-beneficial bacteria that help plants withstand drought. Her literature search regarding isolation and analysis of plant growth-promoting bacteria identifies several leading research groups. Martha emails Professor Jones, at Eastern Coast University in Cascadia, where many fundamental discoveries about plant-beneficial bacteria have been made, to inquire about spending a research visit at the Cascadia lab. Professor Jones replies yes, especially if Martha can obtain funding. With Professor Jones’ support, Martha receives a fellowship from the Cascadian government, to characterize and sequence bacterial strains previously isolated by her supervisor in Alterra. Delighted to gain research experience in a renowned lab in another country, Martha brings bacterial strains with her and the research is successful. The generation of genome sequence data and the collaborative research advances are written and submitted for peer-reviewed publication. The genome sequences are submitted to public sequence databases. Martha returns to her lab, taking some strains from Professor Jones’ lab for completion of her thesis research. The research leads to a potential solution to increase drought tolerance of local Alterra crops. Before she completes her graduate program, Professor Jones visits Martha and her supervisor, giving seminars and meeting other researchers. What began as an email, develops into a long-term research collaboration between research groups in two countries.This collaboration example raises several DSI issues. First, in order for research to be published, genome sequence data must be submitted to public sequence databases. Second, the genome sequence data were generated in a different country to where the strains were originally isolated. Third, the publication of the strains obligates the authors to make those strains available for research purposes. Once sequence information is made public, there is no way to restrict or control use. The only way to restrict use of DSI would be to prevent it from being submitted to databases, which would prevent the research from being submitted for peer-reviewed publication. Without the ability to report research, there would be no interest or value in performing the research and the research collaboration would never happen. This is an example of how DSI could pose an insurmountable barrier to international research collaboration.Box 2History of Data SharingThe development of pure culture methods led by Koch in the 1880s ushered in the transformation of microbiology from a descriptive science to an experimental one [10.Koch R. Methods for the study of pathogenic organisms.Mitt Kaiserlichen Gesundbeitsamte. 1881; 1: 1-48Google Scholar, 11.Koch R. Die aetiologie der tuberkulose.Mitt. Kaiserlichen Gesundheitsamte. 1884; 2: 1-88Google Scholar, 12.Austin B. The value of cultures to modern microbiology.Antonie Van Leeuwenhoek. 2017; 110: 1247-1256Crossref PubMed Scopus (15) Google Scholar]. With cultures of distinct microorganisms, it was possible to characterize them in detail and study the differences in morphology, physiology, metabolism, virulence, and eventually genetics. To facilitate these studies, it was necessary that cultures be freely shared throughout the microbiology community [13.Dedeurwaerdere T. et al.Global scientific research commons under the Nagoya Protocol: towards a collaborative economy model for the sharing of basic research assets.Environ. Sci. Policy. 2016; 55: 1-10Crossref PubMed Scopus (23) Google Scholar]. Sharing of cultures is embedded within microbiology and a publication requirement is that cultures used in a publication must be made available for research purposes; this is sometimes covered by simple MAT. This non-negotiable requirement of microbial resource sharing permits experimental validation of published data and supports follow-up research. The geographic origin of this material is rarely considered, as the resources are to be shared by all.In the 1940s, work by Lederberg and colleagues discovered that bacteria could transfer genetic material between cells [14.Tatum E.L. Lederberg J. Gene recombination in the bacterium Escherichia coli.J. Bacteriol. 1947; 53: 673-684Crossref PubMed Google Scholar,15.Lederberg J. Infectious history.Science. 2000; 288: 287-293Crossref PubMed Scopus (436) Google Scholar]. This research relied on the use of bacterial strains deposited in a culture collection at Stanford University. In order to perform experiments, mutant derivatives were isolated, making phenotypic selection and construction of genetic maps possible. Bacterial genetics led to fundamental discoveries about the nature of genes and the molecular basis of life. All studies were reliant on investigators sharing mutant strains. The collective research led to fuller characterization and deeper understanding of underlying biological mechanisms.The knowledge and tools developed through bacterial genetics led to molecular biology, molecular genetics, biotechnology, and synthetic biology. Recombinant DNA, site-directed mutagenesis, DNA sequencing, PCR, and gene editing are globally used in laboratories for fundamental and applied research. None of this would have been possible without equitable, unrestricted resource sharing between scientists. International research collaborations occur regularly, involving every interaction imaginable. Many are ad hoc, resulting from relationships and interactions occurring within international research communities. The following fictional account illustrates how DSI impacts such collaborations. Martha, a graduate student in Alterra, a semi-arid island nation, is developing her thesis research project on plant-beneficial bacteria that help plants withstand drought. Her literature search regarding isolation and analysis of plant growth-promoting bacteria identifies several leading research groups. Martha emails Professor Jones, at Eastern Coast University in Cascadia, where many fundamental discoveries about plant-beneficial bacteria have been made, to inquire about spending a research visit at the Cascadia lab. Professor Jones replies yes, especially if Martha can obtain funding. With Professor Jones’ support, Martha receives a fellowship from the Cascadian government, to characterize and sequence bacterial strains previously isolated by her supervisor in Alterra. Delighted to gain research experience in a renowned lab in another country, Martha brings bacterial strains with her and the research is successful. The generation of genome sequence data and the collaborative research advances are written and submitted for peer-reviewed publication. The genome sequences are submitted to public sequence databases. Martha returns to her lab, taking some strains from Professor Jones’ lab for completion of her thesis research. The research leads to a potential solution to increase drought tolerance of local Alterra crops. Before she completes her graduate program, Professor Jones visits Martha and her supervisor, giving seminars and meeting other researchers. What began as an email, develops into a long-term research collaboration between research groups in two countries. This collaboration example raises several DSI issues. First, in order for research to be published, genome sequence data must be submitted to public sequence databases. Second, the genome sequence data were generated in a different country to where the strains were originally isolated. Third, the publication of the strains obligates the authors to make those strains available for research purposes. Once sequence information is made public, there is no way to restrict or control use. The only way to restrict use of DSI would be to prevent it from being submitted to databases, which would prevent the research from being submitted for peer-reviewed publication. Without the ability to report research, there would be no interest or value in performing the research and the research collaboration would never happen. This is an example of how DSI could pose an insurmountable barrier to international research collaboration. The development of pure culture methods led by Koch in the 1880s ushered in the transformation of microbiology from a descriptive science to an experimental one [10.Koch R. Methods for the study of pathogenic organisms.Mitt Kaiserlichen Gesundbeitsamte. 1881; 1: 1-48Google Scholar, 11.Koch R. Die aetiologie der tuberkulose.Mitt. Kaiserlichen Gesundheitsamte. 1884; 2: 1-88Google Scholar, 12.Austin B. The value of cultures to modern microbiology.Antonie Van Leeuwenhoek. 2017; 110: 1247-1256Crossref PubMed Scopus (15) Google Scholar]. With cultures of distinct microorganisms, it was possible to characterize them in detail and study the differences in morphology, physiology, metabolism, virulence, and eventually genetics. To facilitate these studies, it was necessary that cultures be freely shared throughout the microbiology community [13.Dedeurwaerdere T. et al.Global scientific research commons under the Nagoya Protocol: towards a collaborative economy model for the sharing of basic research assets.Environ. Sci. Policy. 2016; 55: 1-10Crossref PubMed Scopus (23) Google Scholar]. Sharing of cultures is embedded within microbiology and a publication requirement is that cultures used in a publication must be made available for research purposes; this is sometimes covered by simple MAT. This non-negotiable requirement of microbial resource sharing permits experimental validation of published data and supports follow-up research. The geographic origin of this material is rarely considered, as the resources are to be shared by all. In the 1940s, work by Lederberg and colleagues discovered that bacteria could transfer genetic material between cells [14.Tatum E.L. Lederberg J. Gene recombination in the bacterium Escherichia coli.J. Bacteriol. 1947; 53: 673-684Crossref PubMed Google Scholar,15.Lederberg J. Infectious history.Science. 2000; 288: 287-293Crossref PubMed Scopus (436) Google Scholar]. This research relied on the use of bacterial strains deposited in a culture collection at Stanford University. In order to perform experiments, mutant derivatives were isolated, making phenotypic selection and construction of genetic maps possible. Bacterial genetics led to fundamental discoveries about the nature of genes and the molecular basis of life. All studies were reliant on investigators sharing mutant strains. The collective research led to fuller characterization and deeper understanding of underlying biological mechanisms. The knowledge and tools developed through bacterial genetics led to molecular biology, molecular genetics, biotechnology, and synthetic biology. Recombinant DNA, site-directed mutagenesis, DNA sequencing, PCR, and gene editing are globally used in laboratories for fundamental and applied research. None of this would have been possible without equitable, unrestricted resource sharing between scientists. Given past resource by Northern research it is that resource be of into in have been in the on the physical collection of plant without the or of local as well as or The collection of these plant led to the of or that the of new and Sharing of was As the towards DSI will not require physical material access, which raises for the global in terms of benefits A basic of scientific research is to the for This is one of research by not to it is the of private research. DSI access ability to research the ability to research as the of a project are a in research funding. mandatory DSI sharing and ABS a significant to all research, but international collaborations in Given the CBD has to the DSI of this of uncertainty is in terms of global genetic research. As earlier, open access is a fundamental of international research collaborations. The of resource access will be to the of innovative and contributing to food

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