As technology develops and allows for more sophisticated bioweapons and delivery systems to be created, the Department of Defense (DoD) must maintain the capacity to anticipate these new potential threats and develop methods to counter them. One of these new challenges includes the use of synthetic biology as a weapon of mass destruction (WMD). According to Nature, “syn thetic biology is the design and construction of new biological parts, devices, and systems, and the re-design of existing, natural biological systems for useful purposes .” Therefore, the inherent challenge of pre venting the use of synthetic biology in the development of WMD lies in the fact that it is a dual-use technology, which means legitimate applications can also be used for nefarious purposes .
A significant amount of DoD research is centered on harnessing the beneficial aspects of this technology. For example, The Defense Advanced Research Projects Agency (DARPA) is one of the largest spenders on synthetic biology research in the U.S. . The agency invested $135 million on one synthetic biology related program, Living Foundries, from 2011 to 2016 . In terms of DARPA s annual spending on all synthetic biology programs, the most recent available figure places its 2014 research spending at $110 million . Current DARPA programs regarding synthetic biology include Biological Robustness in Complex Settings , Engineered Living Materials , and Living Foundries , all of which focus on using biological systems to create materials for strategic use in defense applications.
Although these programs, and others like them, are designed to explore the beneficial aspects of synthetic biology, it is important to acknowledge that the facilities in which this research is conducted may be vulnerable to theft or attack by bad actors seeking access to the tools needed for nefarious purposes. In order to prepare for and count er the possibility of a threat from the use of synthetic biology in developing WMD, we must assume that not all individuals, organizations, or governments wish to focus on the non-harmful applications of synthetic biology. Dual-use technologies, such as synthetic biology, create situations that are complex, uncertain, and ambiguous . According to the United Nations Interregional Crime and Justice Research Institute (UNI CRI), synthetic biology tools compound the dual-use nature of standard technology and pave the way for conceiving of biology in increasingly abstract terms” . Accordingly, the potential for bioweapons engineered through synthetic biology has caused concern in many communities.
In 2015, the Global Challenges Foundation listed synthetic biology as one of 12 major global risks, with the possibility of an accident or terror-related incident occur ring within 100 years as more likely than nuclear war . The following year, then Secretary-General of the U.N. Ban Ki-moon delivered a speech on the non-proliferation of WMD. He described the U.N.’s commitment to eliminating WMD and expressed concern with the interface of emerging technologies—including synthetic biology—with
WMD . The current rapid expansion of biotechnology capabilities, such as geneediting (including clustered regularly inter spaced short palindromic repeats, known as CRISPR), coupled with global support among governments and private industry, make the discussion of synthetic biology as a potential emerging technology for the proliferation or enhancements of WMDs an important topic of discussion.
Technology Growth and Funding
An important aspect of assessing the threat of synthetic biology is identifying where research is being conducted, where these capabilities exist, and, as a corollary, where such information is lacking. Synthetic biology research funded by national governments is easier to track than research conducted by private industry as several countries openly report aspects of scientific research funding. Although not comprehensive, Table 1 identifies several state-level organizations funding synthetic biology research programs. Most of these programs also provide details regarding the projects they fund. The paucity of easily accessible information from even relatively open governments illustrates a lack of true awareness regarding global capabilities for synthetic biology research and manufacturing. Furthermore, synthetic biology research is likely supported by the governments of additional countries and agencies, but data are not easy to find or verify. Specifically, there is no publicly available information regarding the capacity for research and development or production of synthetic biology in Iran, North Korea, and Russia.
A much larger challenge exists with assessing the activities of private industry. The private sector is typically not held to the same level of transparency as most national governments unless regulations and statutes require specific reporting. Therefore, although general company location information and spending estimates may be available, specific details regarding research and development projects could be vague. In the U.S., universities are typically more likely than industry to provide information related to research, especially pertaining to government-funded projects; however, in some countries, like China and India, the line is blurred between university and state, increasing the difficulty in accurately assessing not only the level of research and production capacity but also potential threats. The Woodrow Wilson Center for Scholars estimated that in 2013, 192 companies worldwide partook in some aspect of synthetic biology research and development . By 2021, the total market for synthetic biology could reach $11.4 million, with an annual growth rate projected at24 percent .
A system capable of tracking and identifying synthetic biology capabilities is needed to ensure global security. The Synthetic Biology Project, part of the Woodrow Wilson International Center for Scholars, was founded in 2008 to track government entities and companies that conduct synthetic biology research . Its efforts are notable but still fall short, particularly regarding the identification of details for government work and privately funded research and development. This lack of information could hamper the ability of DoD and the intelligence community to track potential threats associated with synthetic biology.
Tools, Applications, and Concerns
In order to understand why there is concern regarding the weaponization of synthetic biology, a brief overview of the technology is needed in order to evaluate the capabilities that could be used for nefarious purposes. Synthetic biology is a set of tools that can be used to create completely new forms of living systems or significantly alter existing ones. Broadly, these tools fit relatively neatly into a cycle composed of three categories: design, build, and test .
In terms of functionality, the design and build phases are the two aspects of synthetic biology that would play a major role in the development of new types of bioweapons, as the conceptualization of prospective organisms or systems would be created in the design phase using a suite of techniques, including: automated biological design, metabolic engineering, phenotype engineering, horizontal transfer and transmissibility, and xenobiology .
Metabolic engineering allows scientists to alter pathways in a cell, which could allow toxins naturally produced by the cell to be more potent, or even allow the cell to create compounds foreign to it, as in the example of opiate-producing yeast . Horizontal transfer and transmissibility allows genes to be move more easily from one organism to another, which has already been modestly demonstrated with the influenza virus [17,18]. Finally, one of the most ground-breaking concepts of synthetic biology involves xenobiology, which is the development and/or use of components that do not naturally occur on Earth . Nucleic acids, such as DNA and RNA, are created from building blocks known as nucleotides, which are composed of phosphate, base pairs (adenosine, cytosine, guanine, thymine, and uracil) and a sugar (deoxyribose or ribose). The arrangements of the base pairs dictates the genetic codes of organisms. Xenonucleic acids (XNAs) are nucleic acids that are not composed of the standard nucleotides because the sugar has been replaced with another type of molecule and are thus artificial and not naturally occurring . These nucleic acids could produce biological components not yet present on Earth, opening up a new world of possibilities in terms of biological agents.
The build function of synthetic biology hosts a variety of tools and techniques used in the construction of pieces , but the most important regard DNA synthesis and gene/ genome editing. The construction of DNA using individual components goes hand-inhand with gene editing techniques, which allow genes of a cell to be modified . A variety of techniques for both are now available , but perhaps the most important advance in gene editing has been CRISPR, which allows for the manipulation of genes relatively easily with little downstream alterations [22,23]. According to the National Academies of Sciences, CRISPR “may allow engineering in many new species, providing convenient paths to the further identification of altered phenotypes via either high-throughput screening or directed evolution of organisms with radically new phenotypes and genome-wide sequence changes .” In regards to gene editing, former Director of National Intelligence James Clapper stated to Congress that “given the broad distribution, low cost, and accelerated pace of development of this dual-use technology, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications” . In fact, the National Intelligence Council has reported that “existential risks” can be found with synthetic biology and genome editing , and a report from the Center for Strategic & International Studies predicted that in a future world, synthetic biology would make it possible to develop “DNA-targeted bioweapons” that could be in the arsenal of non-state actors by 2045 .
One of the greatest concerns regarding synthetic biology is its use as a tool to create virulent pathogens. Furthermore, synthetic biology even goes beyond biotechnology in this capacity because it is not only possible to genetically engineer pathogens to make them more virulent, but synthetic biology makes it possible to actually build pathogens from the ground up. For example, in March 2017 it was announced that researchers were able to build components of horsepox, an extinct member of the pox family of viruses, and assemble them, resurrecting the virus . Horsepox cannot be contracted by humans, but a closely related virus, smallpox, is fatal to humans. Smallpox was eradicated in 1980 , but samples still exist in labs in the U.S. and Russia . Following the terror attacks of September 11, 2001, there was concern that smallpox could be used as a weapon by terror groups . However, an even greater threat, demonstrated by the horsepox experiment, now exists because of synthetic biology. In fact, the World Health Organization released a report in 2015 regarding this new concern for smallpox, stating that “with the development of these technologies, public health agencies have to be aware that henceforth there will always be the potential to recreate variola virus, and therefore the risk of smallpox re-emerging can never be fully eradicated .”
In the short term, it is unlikely that synthetic biology will be used to create entirely new classes of threats, but it could make it easier to produce bioweapons, particularly for less technically skilled people  by minimizing or eliminating traditional challenges that exist to bioweapon proliferation . However, experts have concluded that bioweapons created by synthetic biology are currently too sophisticated to be developed by non-state actors and would likely still need to be supported by state actors [2,31], hence the importance of tracking synthetic biology funding and R&D efforts. The likelihood of terror groups or “garage scientists” developing synthetic bioweapons is low—but possible [2,33]. However, it is more likely that terror groups would either steal synthetic or bioengineered organisms from a reputable facility or acquire them through transactions with rogue nations  or possibly through companies that offer DNA printing services. The misappropriation of research by a disgruntled scientist is also plausible , and an accidental release of an agent created through synthetic biology research could lead to the severe, possibly irreparable, damage to the physical environment [31,34].
Counterproliferation and Mitigation
There has always been an enhanced possibility for biological agents to be used as weapons, thus DoD works to ensure that bioweapons are not created and dispersed. However, as the advent of synthetic biology has created new challenges, additional governmental agencies/organizations have created programs and initiatives tailored to combat the use or misuse of synthetic biology in the weaponization of biological organisms (see Table 2).
Although a robust network of programs has developed to thwart the potential misuse of synthetic biology, experts urge that awareness of proper safety and security procedures is still a necessary first step to preventing the intentional or accidental release of a synthetic threat [2,9,35]. In March 2017, senior members of DoD discussed with Congress programs to counter new threats of WMD posed by synthetic biology . Aside from government-sponsored programs to counter major synthetic biology threats, efforts to understand the work of scientists and researchers who are part of the “do-it-yourself” community are underway . The concept of responsible innovation, the idea that “researchers bear the primary responsibility for the integrity of their work ,” has never been more important research and development. quickens, it is imperative for the U.S. due to the advent of synthetic biology and and its allies to identify new threats by other emerging dual-threat technologies.
Synthetic biology is still in its infancy, which poses a twofold challenge. First, the full capacity, both for beneficial and potentially dangerous uses, is still unknown. Second, since the technology is still nascent, it is difficult to assess tracking methods and gain a strong understanding of how the technology is actually being utilized. In addition, the dual-use nature of synthetic biology poses legitimate concerns regarding how to prevent the potential weaponization of the technology without hindering sound, beneficial research and development.
While several initiatives are underway to minimize the nefarious use of synthetic biology, promoting awareness of the technology and ensuring that proper security, safety, and responsible techniques are being practiced will most likely be the best defense against the development of a new type of super weapon. Inevitably, science and technology change the way wars are fought as new discoveries initially meant for one purpose are often implemented as weapons (e.g., the airplane, the flamethrower, the radio, etc.) .
Therefore, as the pace of innovation quickens, it is imperative for the U.S. and its allies to identify new threats by remaining vigilant, tracking an ever-expanding toolkit, imagining possibilities, and making adjustments as needed, allowing the DoD to continually develop new strategies for countering these new weapons. As Thomas Jefferson said, “… as new discoveries are made, new truths discovered and manners and opinions change, with the change of circumstances, institutions must advance also to keep pace with the times .”
1. Nature. (n.d.). Synthetic biology. Retrieved December 27, 2017, from https://www.nature.com/subjects/synthetic-biology.
2. United Nations Interregional Crime and Justice Research Institute (UNICRI). (2012). Security implications of synthetic biology and nanobiotechnology: A risk and response assessment of advances in biotechnology. Turin.
3. Office of Technical Intelligence. Office of the Assistant Secretary of Defense for Research & Engineering. (January 2015). Technical assessment: Synthetic biology.
4. Si, T., & Zhao, H. (2016). A brief overview of synthetic biology research programs and roadmap studies in the United States. Synthetic and Systems Biotechnology, 1(4), 258-264. doi:10.1016/j.synbio.2016.08.003.
5. Wilson Center. Synthetic Biology Project. (September 2015). U.S. trends in synthetic biology research funding. Washington, D.C.
6. Defense Advanced Research Projects Agency. (n.d.). Biological robustness in complex settings (BRICS). Retrieved from https://www.darpa.mil/program/biological-robustness-in-complex-settings.
7. Defense Advanced Research Projects Agency. (n.d.). Engineered Living Materials (ELM). Retrieved December 28, 2017 from https://www.darpa.mil/program/engineered-living-materials.
8. Defense Advanced Research Projects Agency. (n.d.). Living Foundries. Retrieved December 28, 2017 from https://www.darpa.mil/program/living-foundries.
9. Edwards, B. (2014). Taking stock of security concerns related to synthetic biology in an age of responsible innovation. Frontiers in Public Health, 2. doi:10.3389/fpubh.2014.00079.
10. Global Challenges Foundation. (2015). Global challenges. 12 risks that threaten human civilization: The case for a new risk category.
11. United Nations Secretary-General. (2016, August 23). Secretary-General’s remarks to Security Council Open Debate on the Non-Proliferation of Weapons of Mass Destruction [Statement] New York, NY: Author. Retrieved from https://www.un.org/sg/en/content/sg/statement/2016-08-23/secretary-generals-remarks-security-counReferencescil-open-debate-non.
12. The Wilson Center. (n.d.). Tracking the growth of synthetic biology: Findings for 2013 (Rep.). Retrieved December 27, 2017 from http://www.synbioproject.org/site/assets/files/1309/findings_2013-1.pdf.
13. BCC Research. (January 2017). Synthetic biology: Global markets. Retrieved December 28, 2017 from https://www.bccresearch.com/market-research/biotechnology/synthetic-biology-markets-report-bio066d.html.
14. Synthetic Biology Project. (April 8, 2016). The Synthetic Biology Project at the Wilson Center: Eight years of engagement and analysis. Retrieved December 28, 2017 from http://www.synbioproject.org/publications/eight-years-of-engagement-and-analysis/.
15. National Academies of Sciences, Engineering, and Medicine. (2017). A proposed framework for identifying potential biodefense vulnerabilities posed by synthetic biology: Interim report. National Academies Press. Washington, D.C. doi: https://doi.org/10.17226/24832.
16. Thodey, K., Galanie, S., & Smolke, C. D (2014). A microbial biomanufacturing platform for natural and semisynthetic opioids. Nature Chemical Biology, 10(10), 837-844.doi:10.1038/nchembio.1613.
17. Herfst, S., Schrauwen, E. J., Linster, M., Chutinimitkul, S., Wit, E. D., Munster, V. J.,. . . Fouchier, R. A. (2012). Airborne transmission of influenza A/H5N1 virus between ferrets. Science, 336(6088), 1534-1541.doi:10.1126/science.1213362.
18. Imai, M., Watanabe, T., Hatta, M., Das, S. C., Ozawa, M., Shinya, K., . . . Kawaoka, Y. (2012). Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. doi:10.1038/nature10831.
19. Schmidt, M. (2010). Xenobiology: A new form of life as the ultimate biosafety tool. BioEssays, 32(4), 322-331. doi:10.1002/bies.200900147.
20. Johnson, R. (2015). Unnatural biocatalysts.Nature Chemistry, 7(2), 94-94. doi:10.1038/nchem.2178.
21. Kelwick, R., Macdonald, J. T., Webb, A. J., & Freemont, P. (2014). Developments in the tools and methodologies of synthetic biology. Frontiers in Bioengineering and Biotechnology, 2. doi:10.3389/fbioe.2014.00060.
22. Gupta, R. M., & Musunuru, K. (2014). Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. Journal of Clinical Investigation, 124(10), 4154-4161. doi:10.1172/jci72992.
23. Hsu, P., Lander, E., & Zhang, F. (2014). Development and Applications of CRISPR-Cas9 for Genome Engineering. Cell, 157(6), 1262-1278. doi:10.1016/j. cell.2014.05.010.
24. Clapper, J. R. (February 9, 2016). Statement for the record. Worldwide threat assessment of the U. S. Intelligence Community.
25. National Intelligence Council. (2017). Global trends: Paradox of progress. NIC 2017-001.
26. Center for Strategic & International Studies. (2015). Defense 2045: Assessing the future security environment and implications for defense policymakers. Washington, D. C.
27. Koblentz, G. D. (2017). The De Novo Synthesis of Horsepox Virus: Implications for biosecurity and recommendations for preventing the reemergence of smallpox. Health Security, 15(6), 620-628. doi:10.1089/hs.2017.0061.
28. World Health Organization (WHO). (n.d.). Smallpox. Retrieved December 27, 2017 from http://www.who.int/csr/disease/smallpox/en/.
29. World Health Organization (WHO). (2015). A report to the Director-General of WHO. The independent advisory group on public health implications of synthetic biology technology related to smallpox. WHO/HSE/ PED/2015.1. Geneva, Switzerland.
30. Tegnell, A., Wahren, B., & Elgh, F. (2002). Smallpox—eradicated, but a growing terror threat. Clinical Microbiology and Infection, 8(8), 504-509. doi:10.1046/j.1469-0691.2002.00525.x.
31. Office of the Deputy Assistant Secretary of the Army (Research & Technology). (2017). Emerging science and technology trends: 2017-2047: A synthesis of leading forecasts.
32. Zilinskas, R. A., & Mauger, P. (2015). E-commerce and biological weapons nonproliferation: Online marketplaces challenge export controls to reduce the risk that rogue states or terrorists could acquire the capacityto produce biological weapons. EMBO Reports, 16(11), 1415-1420. doi:10.15252/embr.201541232.
33. Jefferson, C., Lentzos, F., & Marris, C. (2014). Synthetic biology and biosecurity: Challenging the myths. Frontiers in Public Health, 2. doi:10.3389/fpubh.2014.00115.
34. National Intelligence Council. (2012). Global trends 2030: Alternative worlds. NIC 2012-001.
35. National Research Council and National Academy of Engineering. (2013). Positioning synthetic biology to meet the challenges of the 21st century: Summary report of a six academies symposium series. Washington, D.C.
36. Pellerin, C. (2017, March 23). DoD officials discuss countering WMD, threats posed by synthetic biology. Retrieved December 29, 2017, from https://www.defense.gov/News/Article/Article/1128356/dod-officials-discuss-countering-wmd-threats-posed-by-synthetic-biology/.
37. Kuiken, T. (2016, 9 March). Governance: Learn from DIY biologists. Retrieved December 29, 2017, from http://www.nature.com/news/governance-learn-from-diy-biologists-1.19507.
38. National Science Advisory Board for Biosecurity (NSABB). (2008). Addressing biosecurity concerns related to synthetic biology: Draft report of the National Science Advisory Board for Biosecurity.
39. Marcus, L. (2017, March/April). A new chapter in warfare: Technological breakthroughs contributed to making World War I the first modern war. Library of Congress Magazine, 6(2), 8-9. Retrieved December 28, 2017 from https://www.loc.gov/lcm/pdf/LCM_2017_0304.pdf.
40. Thomas Jefferson Memorial Inscriptions. (n.d.). Retrieved December 27, 2017, from https://www.nps.gov/thje/learn/photosmultimedia/quotations.htm.
41. Commonwealth Scientific and Industrial Research Organisation (CSIRO). Retrieved December 27, 2017 from https://www.csiro.au/en/About.
42. Austrian Science Fund (FWF). (n.d). Investigating the biosafety and risk assessment needs of synthetic biology in Austria and China. Retrieved December 27, 2017 from http://www.idialog.eu/fwf.
43. Pei, L., Gaisser, S., & Schmidt, M. (2012). Synthetic biology in the view of European public funding organisations. Public Understanding of Science, 21(2), 149-162. doi:10.1177/0963662510393624.
44. University of Lethbridge. (2015, July 8). Government of Canada announces funding to support synthetic biology maker space. Retrieved December 29, 2017, from https://www.uleth.ca/unews/article/government-canada-announces-funding-support-synthetic-biology-maker-space#.WiHBKbKGNEZ.
45. Ding, M., Song, H., Wang, E., Liu, Y., & Yuan, Y. (2016). Design and construction of synthetic microbial consortia in China. Synthetic and Systems Biotechnology, 1(4), 230-235. doi:10.1016/j.synbio.2016.08.004.
46. Agence Nationale de la Recherche (ANR). (2007). 2007 Annual report. Retrieved December 27, 2017 from http://www. agence-nationale-recherche.fr/documents/ uploaded/2008/ANR-Annual-Report-2007.pdf.
47. Singh, D. & Dhar, P. K. (2013). Exploring the future of synthetic biology in India and its probable pathways from infancy to maturity. Current Synthetic and Systems Biology, 01(01). doi:10.4172/2332-0737.1000106.
48. Remy, E., Mossé, B., Chaouiya, C., & Thieffry, D. (2003). A description of dynamical graphs associated to elementary regulatory circuits. Bioinformatics, 19(Suppl. 2), ii172–ii178.
49. Yartseva, A., Klaudel, H., Devillers, R., & Képès, F. (2007). Incremental and unifying modelling formalism for biological interaction networks. BMC Bioinformatics, 8, 433.doi: 10.1186/1471-2105-8-433.
50. Mori, Y., & Yoshizawa, G. (2011). Current situation of synthetic biology in Japan. Journal of Disaster Research, 6(5), 476-481. doi:10.20965/jdr.2011.p0476.
51. Hooshangi, S. and Bentley, W.E. (2008). From unicellular properties to multicellular behavior: Bacteria quorum sensing circuitry and applications. Current Opinion in Biotechnology, 19(6), 550–555. doi: 10.1016/j.copbio.2008.10.007.
52. The National Academies. (n.d.). Opportunities and challenges in the emerging field of synthetic biology. Retrieved December 27, 2017 from http://sites.nationalacademies. org/PGA/stl/PGA_050738.
53. GOV. UK. Developing novel materials with synthetic biology. (2016, February 9). https://www.gov.uk/government/news/developing-novel-materials-with-synthetic-biology.
54. Defense Advanced Research Projects Agency (DARPA). (n.d.). Safe genes. Retrieved December 27, 2017 from https://www.darpa.mil/program/safe-genes.
55. The National Academies, Committee on Strategies for Identifying and Addressing Biodefense Vulnerabilities Posed by Synthetic Biology. (n.d.). Statement of task. Retrieved December 27, 217 from http://nas-sites.org/dels/studies/strategies-for-identifying-and-addressing-vulnerabilities-posed-by-synthetic-biology/.
56. Jamison, S.R. FBI support to the Biological Weapons Convention. (n.d.). Retrieved January 9, 2018 from https://geneva.usmission. gov/wp-content/uploads/2011/12/ Dec.9-Jamison-Presentation.pdf.
57. You, E. H. (2010, July 9). FBI Perspective: Addressing synthetic biology. [Presentation].
58. Intelligence Advanced Research Projects Activity (IARPA). (n.d.). Finding Engineering-Linked Indicators (FELIX). Retrieved December 27, 2017 from https://www.iarpa.gov/index.php/research-programs/felix.
59. Intelligence Advanced Research Projects Activity (IARPA). (n.d.). Functional Genomic and Computational Assessment of threats(FunGCAT). Retrieved December 27, 2017 from https://www.iarpa.gov/index.php/research-programs/fun-gcat.
60. United Nations Interregional Crime and Justice Research Institute (UNICRI). (n.d.). The Biotechnology Initiative. Retrieved December 27, 2017 from http://www.unicri.it/topics/cbrn/biosecurity/biotechnology.