From undergraduate team coach and Jamboree judge for iGEM
by Prof. John Kenneth Wickiser, Administrative Director, Global Alliance for Preventing Pandemics, Columbia University, USA
Biologists have access to longer and more precisely synthesized DNA quickly and more economically than ever before. The combination of the commercial-off-the-shelf DNA and the new genetic tools using common equipment readily available in high schools and college have empowered young students, junior technical staff, and citizen scientists to engineer living systems producing needed biomolecules, serving as biosensors and reporters, and engaging in far-reaching activities such as the storage of digital information. The same tools and systemic advances assisting the scientists and engineers building systems and producing materials in the name of public good can be used by bad actors with nefarious intent. In this article, I will demonstrate how the bar to genetic engineering has been lowered so that non-experts using common equipment are able to make significant advances in the field.
Dr. George Whitesides spoke as the plenary speaker at the 2011 Chemical and Biological Defense Science and Technology Conference and asked whether we should prepare for a “Black Swan” event – one that is improbable, but catastrophic – or whether it’s more prudent to invest in defending against a threat that is less lethal, but more likely. In doing so, he articulated the challenge of risk assessment and mitigation balancing both the probability and severity of a threat. By their very nature, biological technologies are dual use, so the engineering of biological systems simultaneously impacts tools designed for good and those designed as potential weapons. Synthetic Biology, or SynBio, represents a broad group of molecular techniques involved in the engineering of organisms and components of biological networks contained in, or inspired by, living systems. While the term may have been coined in 1912, the first conference attempting to define and promote SynBio as a technology field was held in 2004 at MIT. Advances in SynBio leverage improvements in computational power, the understanding of fundamental biological processes, and in the instrumentation, modeling, and design tools available to the biotechnology community. The current situation is clear: the bar has been lowered for someone to produce a functioning genetically engineered product regardless of its intended purpose being for good or ill, therefore those responsible for public safety need to prepare for an increase in SynBio-based weapons ranging from nonlethal to catastrophic.
The rise of SynBio work and projects being conducted in the academic community might be assessed using the number of teams competing in the iGEM Jamboree, the annual student-centered competition where teams are judged on their Synthetic Biology projects based on the function of their engineered DNA construct or model of an engineered biological system while including safety and social considerations. The competition has evolved to include high school students and graduate students from across the globe. The number of teams competing in the Jamboree increased each year prior to the SARS-CoV-2 pandemic and in 2021, the number of competitors has recovered to pre-pandemic levels as reflected on the following figure.
The wide variety of topics encompassed by the competing teams is part of the draw for a young person; the competitors are really only limited by their imagination and their ability to transition an idea to a product. For these SynBio experiments, the fundamental product is a synthesized DNA construct inserted into and expressed by a model organism or cell line.
As of 2021, student teams were eligible for free custom DNA synthesized up to 20,000 bases in length designed by the team using one of many opensource DNA design and visualization tools (the entire SARS-CoV-2 genome is about 29,900 bases). So, if a team has a device with a web browser connected to the internet, the modest funds needed for the entry fee, and standard lab glassware and instruments found in most high school and college biology and chemistry labs, it has what is needed to be competitive for an award. Given the ethical, safety, and biosecurity considerations and professional culture emphasized by the iGEM organizational leadership, the lowering of the technological bar and the democratization of the involved science has helped these teams of young students to produce amazing products and systems contributing to the public good and the general body of biological knowledge over the past 19 years. The broader scientific community should take note and model the success of iGEM as an incubuator for ethical, responsible, and innovative research by young people from across the globe.
However, the exact same tools and techniques are available for use by those with nefarious intent, and the ability to produce custom-designed DNA sequences capable of being expressed in a model cell or organism relies only on high school- and college-level skill sets in the lab, internet access, modest financial sums, and access to common supplies and instruments. While the skills, equipment, and instrumentation required to engineer a highly contagious respiratory pathogen significantly reduce the number of people capable of successfully accomplishing the building of infectious disease bioweapons, this number increases each year as advances in genetic and bioinformatics tools and lab instruments progresses at an exponential pace. Further, the traditional view of a bioweapon has been focused on respiratory viruses given their ability to spread through a population quickly and destructively despite communities deploying various nonpharmaceutical interventions such as PPE and disinfection and enacting aggressive contact tracing and quarantining protocols. Unfortunately, this narrow view of bioweapons ignores the non- and less-lethal systems and products more easily produced by less-skilled individuals using more pedestrian facilities and instrumentation. The bad actors seeking to use a biological weapon do so to strike fear into a population while undermining a government or other trusted institution; a bacteria-based weapon system is fully capable of accomplishing these goals even if over a more geographically restricted scope. If the improvement of related technologies continues to progress, the bar to engineering respiratory viruses will also lower, and the question of whether a less-skilled person with only common laboratory equipment can engineer a respiratory virus will change to when a less-skilled person with only common laboratory equipment will do so.
A key technology having lowered the technological hurdles to genetic engineering of living systems is custom DNA synthesis. DNA synthesis companies have comprehensive libraries of human and model organism sequences, and the length and precision of their custom-designed DNA sequences are longer, more precise, and much more inexpensive than they were several years ago. These improvements in the field impact the work directly: what took graduate students and postdocs years to accomplish a decade ago are completed in weeks and months by undergraduates and high school students because the process of gene – and gene system – construction has been improved to the point that designing and purchasing long DNA oligonucleotides is similar to most other commercial goods available through internet storefronts. The efficacy of the algorithms currently in place to monitor and prevent the synthesis of DNA destined for bioweapons are not perfect despite the leaders in the field committing to biosecurity and a culture of ethical and responsible research.
Moreover, with the development of benchtop technologies to synthesize long segments of DNA efficiently, precisely, and inexpensively, the biosecurity safeguards that traditional DNA synthesis companies have put in place are no longer an obstacle. It is unlikely that governments will be able to regulate the production of DNA sequences from benchtop synthesis devices, so tracking the instruments and the precursor chemicals used to create long oligonucleotides will remain the primary means to identify non-commercial producers of custom DNA sequences. The question of how to foster and encourage SynBio work for the public good while simultaneously preventing the use of the same techniques and materials to develop weaponry is becoming more complex and challenging as the fields innovate. Those responsible for public safety should prioritize efforts to monitor benchtop synthesis instruments and their products while continuing to work with the synthesis industry to improve security algorithms overseeing the design and purchasing process.
Over the course of the SARS-CoV-2 pandemic, the public has watched in real time as the public health and biosecurity fields overlap and the lines between naturally occurring and engineered threats has become harder to distinguish. The bar has been lowered to produce beneficent biotools just as it has been lowered to produce bioweapons. To answer Whitesides’ question, it seems most prudent to consider and develop plans to counter bioweapons using the entire severity-likelihood scale from Black Swan event to the spraying of Salmonella on a salad bar 10. How risk mitigation is accomplished effectively, while encouraging scientific and engineering innovation for the public good, remains a challenge and will require a multidisciplinary, flexible, and evolving approach for many years by the international community.
References
References
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5. Data extracted from website https://old.igem.org/Team_List.cgi accessed 2 June 2022.
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9. Safeguarding Benchtop DNA Synthesis, Michael A. Fisher, Lindsay Milliken and Tricia White, July 14, 2021, https://fas.org/blogs/sciencepolicy/safeguarding-benchtop-dna-synthesis/, Accessed 9 June 2022.
10. Török TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow R, Mauvais S, Birkness KA, Skeels MR, Horan JM, Foster LR. A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars. JAMA. 1997 Aug 6;278(5):389-95. doi: 10.1001/jama.1997.03550050051033. PMID: 9244330.
Author: Bio
Dr. J. Ken Wickiser joined the Center for Infection and Immunity from the United States Military Academy at West Point, where he was most recently the Associate Dean for Research, Director for the Academic Research Division, and Professor of Biochemistry. As Associate Dean, Dr. Wickiser was responsible for the safe, legal, ethical, and appropriate conduct of research endeavors at West Point by cadets, staff, and faculty across 13 academic departments and 27 research centers. He also focused on building collaborative teams across disciplines at the Academy with leaders in the fields of science, technology, engineering, math, humanities, and social sciences spanning academia, industry, and government.
Dr. Wickiser also served on the Collaborative Academic Institutional Review Board, Faculty Council, and Academic Research Council at West Point as well as a member of the Office of the Secretary of Defense Biotechnology Community of Interest and the Engineering Biology Research Consortium’s Education Working Group. In 2018, he was the PI of the SynBio team at West Point that won a DTRA Synthetic Biology Award for their department along with the iGEM Bronze Medal Team Award.
