4

Opportunities and Challenges
Emerging via a Networked World

Research in synthetic biology has the capacity to revolutionize our understanding of biological processes and genetics, suggesting a human potential that builds on and beyond evolutionary processes. The environment in which synthetic biologists hope to operate—a decentralized, networked ecosystem unconstrained by the boundaries of traditional research institutions—may be the leading edge of this transformation. Synthetic biology, in the words of Richard Johnson, CEO of GlobalHelix LLC, represents the “new normal” of global research—networked, decentralized, collaborative, and multidisciplinary. The novelty and promise of this environment are cause for both excitement and caution.

Next industry wave. Industry has made significant investments in synthetic biology, with the view that the field, coupled with continuing advances in genetics and systems biology, has the potential to revolutionize the development of products and substances through the application of biologically-based manufacturing. Synthetic biology’s emergence parallels trends in advanced manufacturing in which operations are becoming increasingly global and networked-based.1 With this movement, companies are beginning to commercialize products developed through synthetic biology (See Box 4-1).

By the mid-2000s there were already some 3,000 biotechnology companies globally2 and gene synthesis companies operating in five continents3 and produc-

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1 Shipp, Stephanie S. et al., 2012. Emerging Global Trends in Advanced Manufacturing. Report by the Institute for Defense Analyses, Alexandria VA. March.

2 Finnegan, Stephanie and Karl Pinto, 2006. “Globalisation of biotech offshoring,” Pharmabiz.com. May 16. Online at http://www.goodwinbio.com/web/PharmabizDec06.pdf, accessed December 5, 2012

3 Garfinkel, Michele S., Drew Endy, Gerald L. Epstein, and Robert M. Friedman, 2007. Synthetic Genomics: Options for Governance. Rockville, MD: J. Craig Venter Institute, Center for Strategic and International Studies, and Massachusetts Institute of Technology.



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4 Opportunities and Challenges Emerging via a Networked World Research in synthetic biology has the capacity to revolutionize our under- standing of biological processes and genetics, suggesting a human potential that builds on and beyond evolutionary processes. The environment in which synthetic biologists hope to operate—a decentralized, networked ecosystem unconstrained by the boundaries of traditional research institutions—may be the leading edge of this transformation. Synthetic biology, in the words of Richard Johnson, CEO of GlobalHelix LLC, represents the “new normal” of global research—networked, decentralized, collaborative, and multidisciplinary. The novelty and promise of this environment are cause for both excitement and caution. Next industry wave. Industry has made significant investments in synthetic biology, with the view that the field, coupled with continuing advances in genetics and systems biology, has the potential to revolutionize the development of products and substances through the application of biologically-based manufacturing. Synthetic biology’s emergence parallels trends in advanced manufacturing in which operations are becoming increasingly global and networked-based.1 With this movement, companies are beginning to commercialize products developed through synthetic biology (See Box 4-1). By the mid-2000s there were already some 3,000 biotechnology companies globally2 and gene synthesis companies operating in five continents3 and produc- 1 Shipp, Stephanie S. et al., 2012. Emerging Global Trends in Advanced Manufactur- ing. Report by the Institute for Defense Analyses, Alexandria VA. March. 2 Finnegan, Stephanie and Karl Pinto, 2006. “Globalisation of biotech offshoring,” Pharmabiz.com. May 16. Online at http://www.goodwinbio.com/web/PharmabizDec06.pdf, accessed December 5, 2012 3 Garfinkel, Michele S., Drew Endy, Gerald L. Epstein, and Robert M. Friedman, 2007. Synthetic Genomics: Options for Governance. Rockville, MD: J. Craig Venter Institute, Center for Strategic and International Studies, and Massachusetts Institute of Technology. 25

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26 Positioning Synthetic Biology to Meet the Challenges of the 21st Century ing some 50,000 genes annually.4 Biological products have become economically important. In 2010, it is estimated that the bio- economy in the United States (ge- netically modified crops, biological products, and industrial biotechnology) gener- ated more than $300 billion in revenue (the equivalent of over 2 percent of BOX 4-1 The Commercialization of Synthetic Biology: Amryis, Inc. The commercialization of synthetic biology products is in its very early stages, but both investors and entrepreneurs are exploring opportunities. Amyris, Inc. is using synthetic biology to produce products on a commercial scale. In Shanghai, Lishan Zhao, Head of Enzymology and Protein Engineering, Amyris, Inc., described his company’s work with yeast cells engineered for novel functions. One application is to produce a semi-synthetic version of artemisinin, a chemical traditionally derived from the Chinese wormwood plant. Artemisinin is used in anti-malarial drugs, but the chemical is difficult and expensive to extract. By engineering yeast to produce arte- misinin—a process developed by Amyris’ co-founder, Jay Keasling—Amyris worked to provide a steady, non-seasonal, and affordable supply of artemisinin for use in developing countries. In partnership with the nonprofit organization OneWorldHealth and with a $42.6 million grant from the Bill and Melinda Gates Foundation, Amyris developed the ability to produce artemisinin at a scale suitable for global distribution. Production was managed by the French pharmaceutical Sanofi. Sanofi announced in April 2013 that it has begun large-scale commercialization of artemisinin using a process that is based on the process developed at Amyris. The drug will be sold at a cost. Amyris has also explored yeast-based production of farnesene, an aromatic oil used in fuels, cosmetics, pharmaceuticals, and fragrances. Production, howev- b er, has been inadequate to justify a planned venture into biofuels. Nevertheless, Amyris views synthetic biology as viable technology that offers solutions to global challenges. Recently, for example, the company announced a multi-year agree- ment with the global company International Flavors & Frangrances, Inc. to develop c renewable fragrance ingredients using a synthetic biology platform. “I strongly believe that if we all work together, we can pave the road for synthetic biology to play an important role in replacing petroleum one day,” Zhao said. a UC Berkeley News Center, 2013. “Launch of Antimalarial Drug a Triumph for UC Berkeley, Synthetic Biology,” April 11. Online at http://newscenter.berkeley.edu/2013/04/11/launch-of- antimalarial-drug-a-triumph-for-uc-berkeley-synthetic-biology, accessed May 17, 2013. b Bullis, Kevin, 2012. “Amyris Gives Up Making Biofuels: Update,” MIT Technology Review. February 10. Online at http://www.technologyreview.com/view/426866/amyris-gives-up-making- biofuels-update, accessed March 27, 2013. c CNBC, 2013. “BRIEF-IFF, Amyris to jointly develop ingredients for flavors, fragrances mar- ket,” Business news, April 29. Online at http://www.cnbc.com/id/1006861 85, accessed May 17, 2012. 4 Maurer, Stephen M. et al., 2009, “Making Commercial Biology Safer: What the Gene Synthesis Industry Has Learned About Screening Customers and Orders,” Working Pa- per, online at http://gspp.berkeley.edu/iths/Maurer_IASB_Screening.pdf.

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Opportunities and Challenges Emerging via a Networked World 27 gross domestic product).5 Recently, BBC Research LLC, a market research company, estimated that the global value of the synthetic biology marketplace (including supporting technologies, biological parts, and the products developed using these parts) was $1.6 billion in 2011 and projected that the value would rise to $10.8 billion in 2016.6 Successes with engineered biological systems promise a wide range of applications. For example, a trial of engineered male mosquitoes—described at the London symposium by Luke Alphey, Chief Scientist, Oxitec—resulted in a 90 percent reduction in the population of dengue-carrying mosquitoes in the 16- hectare test area.7 Alphey’s team has suggested using this approach—known as the sterile insect technique—for control of agricultural pests such as moths.8 Industry is continuing to make investments in promising engineered bio- products. Monsanto, for example, recently announced the acquisition of certain microbes developed by Agradis—a synthetic biology company launched by Synthetic Genomics Inc. (SGI) and the Mexican company Plenus, SA. Monsanto also is collaborating with SGI in research on plant-microbe relationships. Other industrial ventures include investments in plant-based production of rubber, bio- based acrylics, “green” chemicals made from biological waste, vitamin pro- duction, and biologically based diesel production using renewable carbohydrates.9 In Washington, DC, Darlene Solomon, Senior Vice President and Chief Technology Officer, Agilent Technologies, a global firm specializing in measure- ment, described Agilent’s analysis of market trends since 1940—including the growth of measurement technology, electronics, chemical analysis, communi- cation and the Internet, and personalized medicine. Solomon projected that the growth of the market for the products of synthetic biology will outstrip growth in all of the other categories. She described synthetic biology as “the next wave,” and noted that biologically-based manufacturing will likely transform the production of all types of products by replacing products made with traditional materials with products made of sustainable materials. This will lead, she concluded, to a more sustainable global economy. 5 Carlson, Rob, 2011. “Biodesic Bioeconomy Update. Document 20110811_01. Biodesic. Online at http://www.biodesic.com/library/Biodesic_2011_Bioeconomy_Update.pdf, accessed December 5, 2012. 6 BCC Research, 2011. Synthetic Biology: Emerging Global Markets. Market report number BIO066B. Online at http://www.bccresearch.com/pressroom/report/code/BIO0 66B, accessed May 15, 2013. 7 Harris, Angela F. et al., 2011. “Field Performance of Engineered Male Mosquitoes,” Nature Biotechnology 29: 1034-1037. 8 Jin, Li et al., 2013. “Engineered Female-Specific Lethality for Control of Pest Lepi- doptera,” ACS Synth. Biol, January 8. Online at http://pubs.acs.org/doi/abs/10.1021/sb30 0123m, accessed March 27, 2013. 9 Biotechnology Industry Organization (no date), “Current Uses of Synthetic Biology for Chemicals and Pharmaceuticals.” Online at http://www.bio.org/articles/current-uses- synthetic-biology, accessed March 27, 2013.

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28 Positioning Synthetic Biology to Meet the Challenges of the 21st Century Engagement by Law Enforcement. The Federal Bureau of Investigation (FBI) has been proactive in its engagement with the synthetic biology policy and research communities. Edward You, Supervisory Special Agent in the FBI’s Weapons of Mass Destruction, Biological Countermeasures Unit, described the Bureau’s involvement with synthetic biology in the context of the FBI’s overall effort to prevent terrorism and ensure the safety of those working in the field. The FBI, he said, maintains a dialogue with scientists, students, and members of the DIY community for the purposes of keeping abreast of current developments and educating the synthetic biologists on the broader security picture. “Many people in the life sciences,” he observed, “have never heard of the Biological Weapons Convention. As sponsors of iGEM,” You said, “we’ve had discussions about this—we need to educate people on these issues” (See Box 4-2). Challenges for Synthetic Biology Unlocking the potential of synthetic biology depends on the development of new interfaces for worldwide collaboration and, most likely, new types of creative commons that allow for flexibility in the regulation and ownership of scientific and technological innovations. Technical Challenges At present, only the leading edge of synthetic biology is visible, and the technical challenges are enormous. Synthetic biologists have yet to develop a broad understanding of the scientific foundations and engineering processes needed to sustain rapid increases in the capacity to engineer biology.10 A chief challenge is that, compared to other engineered systems, e.g., automobiles and computers, biological systems are infinitely more complex and do not behave in a linearly predictable way.11 Working at the molecular and cellular level is very difficult. Moving from the cellular to the systems level—producing engineered tissues, for example—increases complexity by orders of magnitude. The problem, Dr. Elowitz observed, is that even if reliable biological parts were available, scientists lack the knowledge to use them effectively. “Biological functions,” he noted, “are implemented by genetic circuits of interacting genes and proteins. But the circuits in question are often embedded in other complex circuits. We can't see the core design. We only understand a portion of what mammal cells are designed to do.” 10 Drew Endy, Assistant Professor, Bioengineering, Stanford University and President, The BioBricks Foundation. 11 Marc Salit, Research Chemist, National Institute of Standards and Technology.

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Opportunities and Challenges Emerging via a Networked World 29 BOX 4-2 Cooperative Arrangements for Discussions about Benefits and Risks A continuous discussion about biosafety, biosecurity, and risk mitigation is criti- cal to the development of synthetic biology. In the United States, the FBI recently began discussions with amateur synthetic biologists on topics ranging from mitiga- tion of biological risks to the broader topic of ensuring responsible scientific innova- tion. The Bureau holds workshops with the DIY community and has routinely been a sponsor of iGEM. The FBI presence at iGEM has a dual purpose; to discuss security issues with iGEM participants and to allow security agencies to keep pace with rapid advances in the field. Elowitz hopes that by asking new It starts with a fundamental biologi- questions and using the cell-building pro- cal question—how many genes do cess as a means of understanding cell pro- you need to have a functioning liv- cesses, the engineering approach to biolo- ing cell? It’s a simple question gy will provide new insights into the about an important biological prob- fundamentals of genetic design. lem, and people will continue to Dr. Solomon reminded symposia work on it without worrying about whether you can use it to make bio- participants that many apparently ubiqui- fuels. tous technologies took years to reach ma- turity. In the particular case of synthetic Peter Leadlay, biology, she said, both the development of Cambridge University large-scale applications and the market penetration of these applications will take decades (See Box 4-3). She noted, how- ever, that advances in synthetic biology will likely be accelerated by the parallel growth of related technologies, such as DNA sequencing and computing. In the interim, she said, synthetic biology (as is the case with other emerging technolo- gies) must necessarily move forward incrementally. Parts and Applications. An immediate challenge for synthetic biology is the development of a large portfolio of standardized, modular biological parts and tools that behave predictably and may be used in a wide range of applications. Though thousands of biological parts have been cataloged—over 10,000 in the Registry of Standard Biological Parts,12 for example—reproducible, reliable parts are still not widely available. 12 This searchable registry is the best-known of a growing registry of biological parts. It contains some 2,000 “BioBrick,” parts, devices, and systems. The availability of these biological parts eliminates the need to develop each biological part separately, resulting in significant time savings. In standard biology, for example, it might take a month to assemble a given biological part. Using parts from a registry, a synthetic biologist can assemble 20 parts over the same period. See http://partsregistry.org. The parts in partsreg- istry.org were moved to parts.igem.org in May 2013.

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30 Positioning Synthetic Biology to Meet the Challenges of the 21st Century BOX 4-3 What Can We Expect from Synthetic Biology? Participants in the symposia—while acknowledging the difficulty of prediction in synthetic biology—suggested possible short- and long-term developments in the field. In 5 years?  Multiple global intercommunicating synthetic biology research platforms, including public-benefit facilitities In 10 years?  $20 billion in synthetic biology products  Cells routinely engineered to produce desired bulk and fine chemicals In 20 or 30 years?  Rationally engineered multi-cellular tissues or organs  Widely deployed cellular computing systems  Novel biological manufacturing processes for non-biological products The first tools and applications of synthetic biology are being developed at the molecular and cellular level. The “wish list” for synthetic biology is long, including not just interchangeable biological parts and systems, but also custom- ized cellular functions and designed bacteria and other organisms that can be used to speed chemical production—in, for example, for industrial processes. Multi-cellular development, tissue engineering, and industrial applications lie in the future, but will inevitably depend upon investments made now.13 While the ultimate products of synthetic biology are still unknowable, the immediate utility of synthetic biology—designing and constructing biological parts to in- crease our understanding of fundamental biological processes—is already be- coming manifest. At this moment, Dr. Endy observed, the immediate benefits of synthetic biology research include a greater understanding of how living organ- isms work. Inter-operability. Richard Kitney, Professor of Biomedical Systems Engi- neering and Senior Dean and Director of the Graduate School of Engineering and Physical Science, Imperial College London, stated that a key to the success of synthetic biology will be the development of standardized biological parts that can be reliably combined as modules and adapted as necessary. To become universally accepted and used, every element of designed parts and systems, databases, measurement units, and scalable systems must be compatible, and compatibility must extend across scales and levels—from molecular- to tissue- level, from lab to lab, from one operating system to another, and across regions 13 Darlene Solomon, Senior Vice President and Chief Technology Officer, Agilent Technologies.

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Opportunities and Challenges Emerging via a Networked World 31 and countries. At present, Kitney noted, the modularity of biological parts is considerably limited, in part because of the complex interactions that occur among biological parts. Kitney stressed the need to increase understanding of how biosynthetic pathways function and to find new ways to test and control the interactions of synthesized biological material. Karmella Haynes suggested that a first step to achieving this goal could be a requirement that a rigorous, standardized charac- terization accompany any biological part entered in a registry. In addition to a common language, Haynes continued, the success of the field will depend on standardized descriptive protocols. She suggested, for example, that each de- scription for a biological part listed in a registry or database should include a common set of information. Solomon commented that historically, timing the development of stand- ards has been a balancing act for developing technologies—whether to stay open in terms of standards, because the knowledge base is still developing, or to de- velop convergent standards that improve efficiency. Marc Salit, Research Chem- ist, National Institute of Standards and Technology, reminded participants that existing standards institutes can serve as a resource and provide methodologies for the development of interoperable modular parts. A possible place to begin, he added, would be in areas with the potential for commercialization. Measurement. The accurate measure of systems performance is an im- mediate and pressing challenge in synthetic biology. In Washington, DC, Peter Carr, Senior Researcher, Massachusetts Institute of Technology Lincoln La- boratory, noted that reliable measurement standards are a critical factor in a biologist’s ability to replicate biological parts. The biology community, he said, is still learning to think like engineers, for whom measurement of sys- tems performance is standard. Measurements of the performance of the syn- thetic part or system and of the individual parts that contribute to the system’s performance are required. It would be useful, Carr noted, to create cells and sensors that perform logical operations as well as those that can report back on the performance of the operation. The ability to receive feedback from a sys- tem is crucial, Carr observed, especially in the context of living cells, given their range of complexity. Carr’s co-panelists agreed that it is essential to have an infrastructure ca- pable of supporting multiple types of metrics including:  The number of parts, their designs, their construction, and the extent of their utilization  The actions and results of tools used for computing, scanning, and com- munication  The interconnective capacity of biological parts across scales and across national borders

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32 Positioning Synthetic Biology to Meet the Challenges of the 21st Century Reshma Shetty, Co-founder, Ginkgo BioWorks, encouraged participants to take advantage of measurement improvements currently in use in gene sequencing and mass spectrometry. She also suggested several measurement priorities: acquir- ing measurements of all engineered cell strains; focusing on 100 important cell proteins; designing a “stress test” chassis explicitly for measurement; and rede- signing cells for measurement. In the future, global acceptance of the units of measure will be as vital as the measurements themselves. François Képès, Research Director, Centre Nacionale de Recherche Scientifique (National Center for Scientific Research), noted the importance of developing standardization, akin to the universality of the chemical formula for water, to ensure that global collaboration flourishes. Cost Control for Scale-up. Since the early days of genome sequencing, DNA sequencing costs have fallen dramatically. The sequencing of a genome can now be completed within two weeks at a cost of less than $10,000. The pro- ject to sequence the human genome, by contrast, took 13 years and cost $27 billion.14 These decreases in time and cost coupled with early successes in the production of commercially important chemicals (such as biofuels, agricultural products, and medicines) fueled industry investment in synthetic biology. However, cost-effective production of industrial chemicals requires engi- neering of highly efficient microbial strains.15 The development of a viable product containing synthetic parts, however, remains a “herculean” effort, said Endy, who observed that it cost $25 million to genetically engineer E. coli and yeast to produce the chemical precursor to the antimalarial drug artemisinin. At this early stage of its development, synthetic biology generally has a modestly scaled production capability and a decentralized structure with devel- opments taking place in multiple locations, Solomon said. For fields such as specialty chemicals, pharmaceuticals, and agriculture, or for fuel production in developing economies, the current scale is adequate, she said. In the case of re- newable energy in more mature economies, however, large-scale production may require government subsidies. Professor Kitney suggested that the cost problem may be solved as biological parts proliferate and become more refined. Tools and Software. Improved data-gathering tools, software, and hardware are as important to the development of synthetic biology as improvement in the modularity of biological parts—especially if the ultimate object is industrializa- tion.16 A number of labs and researchers have developed online tools for use in developing and working with synthetic biology products. These include DNA 14 The Human Genome Project, completed in 2003, was a 13-year collaborative project coordinated by the U.S. Department of Energy and the National Institutes of Health, with contributions from the U.K.’s Wellcome Trust as well as China, France, Germany, Japan, and others. The project's goals included identifying and storing information on all the genes in human DNA. Analysis of the data is continuing. See http://www.ornl.gov/sci/ techresources/Human_Genome/home.shtml, accessed March 13, 2013. 15 Lishan Zhao, Head of Enzymology and Protein Engineering, Amyris, Inc. 16 Kitney.

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Opportunities and Challenges Emerging via a Networked World 33 assembly programs, applications for modeling protein structures, and biological parts registries.17 However, the growth of synthetic biology is inhibited by a lack of field specific computational tools, e.g., computer-assisted design and modeling tools18 as well as automated processes that can reduce the cost of synthesizing biological parts.19 There is also a need for software that allows communication among multiple complex datasets,20 and for linked software/hardware systems that can feed information back into biological models.21 Other enabling technologies include faster, cheaper DNA sequencing technologies, improved software for de- signing and simulating biological systems and circuits, and improved measure- ment technologies.22 Regulatory Challenges Because the boundaries of synthetic It isn’t just that the future of synthet- biology are so fluid, the field may not fit ic biology is uncertain—there’s no neatly within existing regulatory frame- way we can know the future. So works. In the United States, under the cur- regulatory regimes must be open, rent regulatory framework for biotechnol- adaptive, and dynamic. ogy, the Department of Agriculture, Food and Drug Administration, and Environ- Nikolas Rose, Professor of Sociology and Head of the mental Protection Agency are responsible Department of Social Science, for oversight of genetically modified ani- Health and Medicine, King’s mals, plants, and microbes. Recently, poli- College, London cymakers have begun to focus on the regu- lation of synthetic biology and are considering whether and how current regula- tions apply to the products of synthetic biology. In the U.K. and China, legislators have developed strategic plans designed to advance synthetic biology. Recognizing that science tends to move forward much faster than policy formation, early attention to issues associated with the governance and regulation of synthetic biology seem to be particularly appropriate. Patrick Boyle, Postdoc- toral Fellow, Wyss Institute for Biologically Inspired Engineering, suggested that it would be best for synthetic biologists to continue their efforts to engage with regulatory bodies now, before the number of products becomes overwhelming.23 17 OpenWetWare, a project to promote information-sharing among researchers in biology and biological engineering. Online at http://openwetware.org/wiki/Synthetic_Biology:Tools, accessed Marcy 27, 2013. 18 Cesar Rodriguez, Senior Research Scientist, Autodesk. 19 Todd Peterson, Vice President, Synthetic Biology R&D, Life Technologies Corpora- tion. 20 Peterson. 21 Reshma Shetty, Co-founder, Ginkgo Bioworks. 22 Syntheticbiology.org. Online at http://syntheticbiology.org/FAQ.html, accessed March 27, 2013. 23 There are numerous examples of engagement between those representing the inter- ests of the synthetic biology community and regulatory bodies. The U.S. Department of

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34 Positioning Synthetic Biology to Meet the Challenges of the 21st Century Boyle suggested that one approach might be to build legislation around prototypes, such as synthesized molecules shown to be safe. Intellectual Property Issues Questions about Property. The concept of constructing new biological parts raises questions about whether rights to parts should be privately owned, how the parts should be registered, whether they should be patented, and how different intellectual property and sharing arrangements will affect advances and innovation in synthetic biology. Patent law is not uniform globally. At the Shanghai symposium, Gordon Zong, Managing Director of The Office of Technology Transfer at Shanghai Institutes for Biological Sciences and Adjunct Professor at Shanghai Intellectual Property Research Center, noted that in China, intellectual property law is not well developed and that patent considerations have not played a large role in the early stages of developments in synthetic biology. Rochelle Cooper Dreyfuss, Pauline Newman Professor of Law, New York University School of Law, noted that, in the case of biological materials, U.S. intellectual property laws present a kind of double-edged sword. On one hand, she said, knowledge about the struc- ture and function of biological elements such as proteins and genes is valuable. Conferring patent or copyright protection can encourage both investment and innovation. On the other hand, she observed, securing a patent may be a lengthy and costly process wherein the benefits of securing a patent do not justify the associated investment of time and capital. In the United States, the pace of biological discoveries has tested intellec- tual property statutes. A watershed event was the 1980 Supreme Court case Di- amond v. Chakrabarty. In this case, the Court ruled that “a live, human-made micro-organism is patentable subject matter.” This opened the door to the pa- tenting of modified plants and animals (although, under the 13th Amendment to the U.S. Constitution, human beings cannot be patented). Individual genes are eligible for certain patent protections. Today, about 20 percent of human genes (some 4,000 genes) are mentioned in patent claims.24 Speaking in Washington, DC, Arti Rai, Elvin R. Latty Professor of Law, Duke University School of Law, Health and Human Services, for instance, developed its 2010 Screening Framework Guidance for Synthetic Double-Stranded DNA Providers with input from, among others, the International Gene Synthesis Consortium, the International Association for Synthetic Biology, and the International Council for the Life Sciences. 24 The patent claim describes the scope of protection granted in a patent. The holder of a gene patent does not own the gene, as is widely believed—that is prohibited—but can claim man-made or isolated DNA molecules as well as novel ways to use them. Patent infringement is not a risk in whole gene sequencing in general, but may be a risk where a sequence being used corresponds to a portion of a human gene. See Holman, Christopher, 2012. “Debunking the myth that whole-genome sequencing infringes thousands of gene patents,” Nature Biotechnology 30(3): 240-244. March.

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Opportunities and Challenges Emerging via a Networked World 35 stated that around 60,000 patents have been issued for DNA-related innovations. Co-panelist Daniel Kevles, Stanley Woodward Professor of History, Yale Uni- versity, observed that the problem for synthetic biology is that the patent system, in granting broad rights to a patent holder, may, as a result, limit and prohibit researchers’ and the public’s full access to the potential benefits of the field. Linda Kahl, Legal Scholar, Department of Bioengineering, Stanford Uni- versity, observed that the U.S. patent system was not designed to handle the complex intellectual property issues that arise in the practice of synthetic biolo- gy. The practice of synthetic biology, she continued, entails three major process- es: abstraction (developing low-complexity biological parts, devices, and sys- tems); decoupling (obtaining specific DNA sequences that are distinct from the natural DNA design); and standardization (uniform composition and function of biological parts). She noted that these processes can enable non-biologists to generate organisms, such as a bacterium that destroys tumors, without needing special knowledge about DNA and genetics. She observed, however, that within the patent system, each process can be hindered by high costs and the threat of patent infringement:  Abstraction: The availability of simple biological components allows non-biologists to generate organisms, such as tumor-destroying bacte- ria, without needing special knowledge about DNA or its functions. Registries provide information or materials, but conducting freedom-to- operate searches (searches to determine whether a product infringes claims on patents already issued) can run into thousands or tens of thousands of dollars. Royalty stacking (when a single product may po- tentially infringe on multiple patents) may add costs that make it cost- prohibitive to market a product.  Decoupling: Specialists can now develop software to design specific genetic sequences that can then be ordered from DNA synthesis com- panies—exponentially increasing the speed of DNA production and testing. However, in producing the genetic material, synthesis compa- nies may inadvertently infringe on patented sequences.  Standardization geometrically increases the quantity of parts being produced, distributed, and re-used. Synthetic biologists are developing standards for the physical composition of parts, but there are many types of standards—functional standards, for instance—that may be subject to patent hold-ups if an uncooperative third-party patent holder were to refuse to issue a non-exclusive license to use, for example, a standard bacterial promoter that measures and reports on the relative activity of a sample promoter. Thus, a major question for researchers is whether synthetic biology can thrive within existing intellectual property systems or whether a new national or inter- national intellectual property framework is needed. In synthetic biology, the

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36 Positioning Synthetic Biology to Meet the Challenges of the 21st Century resolution of intellectual property issues is especially important given the num- ber of synthetic parts already developed (over 10,000 in the iGEM Registry alone) and the strong interest in eventually commercializing these products. Over the course of the three symposia, Professor Dreyfuss, Nita Farahany, Associate Professor of Law and Associate Professor of Philosophy, Vanderbilt University, and Mark Lemley, William H. Neukom Professor of Law, Stanford University, suggested several ownership alternatives:  Registering new parts in a searchable clearinghouse that provides par- tial or conditional exemptions for information providers, intermediar- ies, users, and contributors  Depositing standard parts in an information commons available to members who share costs and profits  Research and educational patent exemptions  Copyrights and utility model (shorter-term) patents  Petty patents, which are regulated but do not require patent examination  Obligations for funders and investors to make resources available through non-exclusive licensing  Development of software tools for the patent environment. Keep in mind a vision we’d like to strive towards: imagine creating a collection of genetic functions that we’re free to use and compose—free of fear of liability, limi- tation of uses, and transaction costs. Linda Kahl, Legal Scholar, Department of Bioengineering, Stanford University Inclusiveness Synthetic biology is a hybrid field that grew out of and feeds back into a range of disciplines. Continued inclusiveness is essential for the field’s continued growth. Engagement with the Business, Regulatory, and Policy-Making Communi- ties. Many symposia participants emphasized that continued investment and buy- in by industry and policymakers is essential for the development of synthetic biol- ogy. At the three symposia, presenters representing petroleum, microchip, and genetic synthesis organizations, business collectives, and national and regional trade organizations described potential alliances and strategies that might strength- en synthetic biology. In Washington, DC, Lionel Clarke, Biodomain Global Strategic Programme Manager, Shell Global Solutions, observed that industry views synthetic biology as a promising field with the potential to offer solutions to many problems. Unfor- tunately, Clarke observed, at present large companies only have the infrastructure

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Opportunities and Challenges Emerging via a Networked World 37 for existing technologies. Readying synthetic biology for the market, he said, would require simultaneous progress along many fronts—development of bench- marks, partnerships with industries, capital investment, and proof of effective- ness—to achieve a technological “push” met by a market “pull.” Ian Fotheringham, President, Ingenza, observed that, while many large companies are interested in using biological tools, they have shared concerns about high costs, feasibility, and reliability. Fotheringham suggested addressing these concerns by furnishing evidence of the reliability of a given product, de- fining approaches that increase the speed of production while reducing costs and risks, and ensuring a clear agreement about the allocation of intellectual proper- ty. Furthermore, he suggested that managers need to build interdisciplinary teams and network actively to find new users and remain current on developing trends. Engaging the Public. At the symposia, considerable attention was paid to involving a larger community of stakeholders in discussions about synthetic biology. One reason for paying attention, said Jaydee Hanson, Policy Director, International Center for Policy Assessment, is that the public has a right to know about publicly funded research. Hanson called for a moratorium on the use of synthetic biology to change human genetic makeup and cited several possible dangers inherent synthetic biology, e.g. the unintended effects of exposure to synthetic organisms that have not been proven to be safe; potential misuse, in- equitable distribution of beneficial products from the technology; and a lack of clarity about how to maintain public health and worker safety. An important part of any discussion Something we don’t always appre- with the public includes addressing con- ciate is the power of convening— cerns about biosafety and biosecurity. working cooperatively and leaving There is an excellent opportunity, Solo- institutional baggage at the door. mon observed, for a global collaboration to improve communication about synthet- Robert Wells, former Head, Biotechnology Unit, Directorate for ic biology. She noted that a bad outcome Science, Technology and Industry, for an engineered biological product can Organisation for Economic Co- quickly go viral but observed that the operation and Development Internet is equally effective as a tool for spreading news about the benefits of synthetic biology. Laurie Zoloth, Professor of Medical Humanities & Bioethics and Religion and Director, Center for Bioethics, Science and Society, Northwestern University, suggested six points to consider on the ethics of science and synthetic biology:  What methodologies and paradigms should the field adopt?  Is there a moral problem with creating life?  What ideas of justice would work for the field?  When are the risks that will arise morally justifiable?

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38 Positioning Synthetic Biology to Meet the Challenges of the 21st Century  How can we interpret and address moral and religious concepts on what constitutes life, safety, and social values?  How will the field be regulated? Synthetic biologists recognized early the importance of public acceptance in preparing to commercialize synthetic biology products. Experiences with the European rejection of genetically modified food, for example, illustrate the per- ils of not involving the public often and early in discussions about emerging technologies. Since the public pays for a large proportion of research funding and is, ultimately, the beneficiary of the research or the consumer of products that result (and sometimes the bearer of the burdens of technologies gone wrong) many symposia speakers agreed that the public must be included in dia- logues about synthetic biology, its limitations, and its future. Professor Qiu noted the urgency of having stakeholder input and true part- nerships with the public, nongovernmental organizations, and the media—with mutual learning on all sides. Besides discussing the balance of risks and bene- fits, Qiu said, partners should discuss ethical issues—such as how to ensure that synthetic biology benefits a whole society (rather than benefitting a select few). Joy Zhang, BIOS Centre, London School of Economics and Françoise Roure, Chair, Committee on Technologies and Society, French High Council for Indus- try, Energy and Technologies, discussed to the effects of including sociologists and ethicists in discussions on synthetic biology. These are fields, she observed, that can help in discussions about the intersections between science and justice, the morality of creating life, and the moral obligations of science and society in the metamorphosis of technology. Preparing for a Networked World Advancement in synthetic biology requires more than collaboration: it re- quires practitioners who are prepared to maximize the benefits of working across disciplines. While this implies changes in education, it may not necessari- ly suggest the need for a new degree curriculum in synthetic biology. Gautum Mukunda, Assistant Professor in the Organizational Behavior Unit, Harvard Business School, suggested that one model might be a kind of networked curric- ulum in which students of various disciplines work together and learn to under- stand both the fundamental principles of several fields and the strengths that each discipline can bring to new research. A skill set would likely extend be- yond the natural sciences—for example to include the social and behavioral sci- ences—and students might have the opportunity to work with experienced men- tors and researchers from various countries. Foundational skills for young researchers might also include an understanding of the regulatory environment and the ability to assemble an effective team.

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Opportunities and Challenges Emerging via a Networked World 39 The iGEM model, with its emphasis on projects that may yield “real- world” applications, has worked well. The current generation of students may have a more ready understanding of how science can affect the world around them. However, symposia participants suggested that other models—perhaps along the lines of the competitions run by engineering schools25—might enrich the field. These included:  A program that features a course combining engineering design with communication and is taught by faculty in both specialties, a model used at Northwestern University, that might be appropriate for graduate and postdoctoral students.26  The Engineering Research Center at the National Science Foundation (NSF), which provides on-campus centers for cross-disciplinary exper- imental research. The centers expose students to the nature and prob- lems of cross-disciplinary research and provide opportunities to learn from experts in industry and academia.27  The NSF’s Ideas Factory Sandpit, which fosters high-risk, high-reward research that would otherwise not receive support. This model facili- tates interdisciplinary research on global problems and has led to col- laborative multi-country projects.28 Several symposia participants endorsed the importance of agreeing on milestones to help guide the development of synthetic biology. Dr. Clarke said that as part of a move toward a market, roadmaps can support development of an emerging field by simultaneously addressing goals and synergies. A roadmap can identify short- and long-term goals and help create communities that are focused on those goals. However, too close a focus could undermine innovation, he added. The ideal roadmap is not a straitjacket but a marker showing targets to address but also allows shifts to other areas as the knowledge base grows, or as breakthroughs occur, said Guo-ping Zhao. Richard Johnson suggested that the best way to advance synthetic biology would be to produce a consensus-based global roadmap. While doing so will be complicated, there are numerous exam- ples of roadmaps that address aspects of this complexity—such as those of the U.S. National Weather Service, the National Aeronautics and Space Administra- tion, and the Cloud Computing industry.29 The urgency of engaging multiple 25 Karmella Haynes, Assistant Professor, School of Biological and Health Systems Engineering, Arizona State University. 26 Michael Jewett, Assistant Professor of Chemical and Biological Engineering, Northwestern University. 27 Sohi Rastegar, Acting Division Director, Office of Emerging Frontiers in Research and Innovation, Directorate for Engineering, National Science Foundation. 28 Rastegar. 29 Johnson, Richard A., 2012. “Enabling the Synthetic Biology Commons: The Role of a Strategic Global Roadmap” (draft).

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40 Positioning Synthetic Biology to Meet the Challenges of the 21st Century stakeholders, noted Johnson, comprises in itself a way to enrich and enhance the field and its potential as more and more partners share their expertise. [Synthetic Biology] is a very exciting enabling technology. It […has] the potential to drive a new industrial revolution for the 21st century […,but] we,…both in Britain and across the world, have a responsibility for the right regulatory environment which enables rapid scientific progress whilst ensuring public safety and confidence around… ethical issues. David Willetts, Minister for Universities and Science, U.K. Government