Reading guide: Skip the bullet points to skim through

Aim

This article aims to synthesize various sources to inform an “inside view” on how likely is it that an individual, group, or country would be able to successfully start a pandemic given current and emerging technologies. 

Through this post, I hope to inform EAs' personal assessments of whether existing measures to prevent bioweapon development and use are sufficient, but leave open the question of whether existing measures to detect and respond to the outbreak would effectively limit casualties from such a scenario. 

The purpose of this piece is not to advance scientific knowledge, or advocate for certain policies. Instead, it is meant to empower non-technical EAs with a more empirically grounded sense of how important and urgent biosecurity is, in light of emerging technologies. I hope this post also contributes to discussions on how to consider and weigh various interventions, and serve as an entry-point for further research. The information here can also be used in conjunction with “outside view” priors to develop numerical estimates.  

I caveat that this is the perspective of someone who has zero technical expertise in biology, but I have tried to rely on credible secondary sources and sought out more experienced individuals, in forming my opinions that follow. 

Overall Assessment (epistemic status in italics)

While states generally seem unwilling to use bioweapons to inflict the maximum number of casualties possible, there are likely to be a few terrorist groups/individuals who would intend to do so if they possess the required capabilities. It is quite concerning that the barriers to starting a pandemic by weaponizing existing viruses already seem quite surmountable today for state or state-sponsored actors, and insider lone-wolf scientists who turn to terrorism (low ; why has there been no attempts to do so yet since the 2010s?).

At present, the barriers to engineering a pathogen with increased contagiousness, deadliness or antiviral immunity still seem quite insurmountable unless the bioweapons programme is a multi-year state-led/state-sponsored one (medium).

However, the publication of gain-of-function research, development of high-throughput automation of testing processes, and progress in understanding of genotype-phenotype relationships, could lower the barriers for engineering pandemics quite significantly in the coming years. Without appropriate regulatory intervention, these three scientific-technological developments are likely to continue to advance rapidly. 

Intention of State Actors

States seem somewhat unwilling to use bioweapons, especially contagious pathogens, on a large-scale. (I note that this section is currently underdeveloped and will incorporate additional research in due course)

• Many states (esp. Great Powers, e.g. US) have had bioweapons programmes 
  • The USSR carried out massive bioprogramme and genetic engineering including weaponising cockroaches, even after signing the Bioweapon convention
  • For non-Great Powers, bioweapons can be a "poor man's nuke" (i.e. asymmetric weapon) e.g. North Korea 
• However, there have been no instances of large-scale usage of bioweapons in international warfare since the 1940s (after Japan's use on China); there were not even close calls. Bioweapons were virtually never included into war plans, nor prepared for usage. ^[1]
  • There may have been some sort of Taboo on bioweapons due to humanitarian or religious reasons, that make usage very politically costly. 
  • In addition, the BWC further deters states from producing, let alone deploying bioweapons. 
• There may also be further incentives not to use contagious pathogens, as the outcomes are hard to control. 
  • Biotechnology advances may eventually allow actors to design a bioweapon to target particular sub-populations based on their genes or prior exposure to vaccines, reducing the barrier due to concern about contagious viruses being uncontrollable.^[2]

Intention of Non-State Actors

There are very likely to be at least some terrorist groups or individuals that intend to use bioweapons for catastrophic outcomes.

• Groups such as al-Qaeda and the self-proclaimed Islamic State have reportedly called on “scientists, doctors, and engineers to join their cause, which includes the use of specialized skills to inflict harm.”^[3] Aum Shinrikyo (now defunct) had tried to carry out Biological attacks using Botulinum and Anthrax.^[4]
• Most attempts to use biological agents against humans in terrorist attacks in the past have been small-scale, low casualty events aimed at causing panic, and disruption rather than excessive death tolls. Recent research points out that there has only been one documented death attributable to biocrimes (murder of Hungarian dissident Georgi Markov in London in 1978; although that is debatable), a number of bioterrorism incidents with no directly associated deaths, in the United States^[3] and five deaths from a documented lone-wolf terrorist incident (i.e. Anthrax letters).
• However, there are certain terrorist groups that are likely to aim for maximum catastrophe, including through the use of biological weapons. These groups, such as apocalyptic cults (e.g. Aum Shinrikyo) and extreme environmental groups,^[5] tend to have maximalist ideologies aimed at cosmic change and/or misanthropic goals.^[6] 

Capability of State and Non-State Actors

Since the Cold War, state actors were already able to weaponize natural pathogens (though they found engineering pathogens challenging). 

• The Soviet Union, which had the largest and longest-running program, lasting sixty-years and with an estimated investment of $35 billion, did not manage to move beyond the exploratory phase for engineered pathogens (the program's main focus).^[7]
• But the Soviets did manage to weaponize at least eight natural agents: B. anthracis (anthrax), F. tularensis (tularemia), Y. pestis (plague), Coxiella burnetii (Q fever), Brucella suis (brucellocis), VEE (Venezuelan equine encephalitis), botulinum toxin, and variola virus. 
• They had also designed several dissemination systems for these agents, including spherical bomblets, cluster bombs for delivery by aircraft, and spray tanks carried by medium- range bombers.
• The American programme lasted twenty-seven years and costed $700 million. Among the two dozen agents studied, only seven human non-contagious agents were produced and weaponized, while five anti-crop agents were standardized and produced but not weaponized. It is generally believed that weaponization within the U.S. bioweapons program centered on agents for which countermeasures were available or could be developed to protect the troops, and that although contagious diseases such as plague and smallpox were studied, they were not weaponized.^[7]
• These cases show that from as early as the 1970s, states at the forefront of biotechnology were more than capable of weaponizing natural pathogens. 
• Since then, numerous scientific breakthroughs that made it much easier for scientists to 'engineer' pathogens (see section on “current barriers and affordances of emerging technologies”).

Historically, Non-State Actors lacked capabilities to use bioweapons for mass destruction. 

• Until about the 2000s, barriers to large-scale bioweapon attacks had posed insurmountable for non-state actors. Aum Shinrikyo tried in the 1990s but failed to:^[4]
  • Obtain the appropriate strains of C. botulinum and Anthrax (due to hazmat controls)
  • Convert benign (vaccine strain) anthrax to a lethal form via transduction ("Makino recalled that...a skilled co-worker...had to spend six months in a leading laboratory at the Pasteur Institute to learn the nuances of the virus-mediated transduction methods. Even then, Makino described the transduction procedure as 'very inefficient'.")
  • Achieve the specific culture conditions required for the production and storage of toxins by C. botulinum/reproduction of Anthrax 
  • Concentrate the toxins enough to have noticeable effect
  • Disseminate the material (The cult considered buying a high-powered sprayer from a European firm...[but] this would entail a two-month delay)
• However, the standard approach of using historical incident data or case studies of terrorist attacks or bioarms programs may not take account of radical developments in biotechnology, especially since DNA was first sequenced in 2003.

Current Barriers and Affordances of Emerging Technologies (incl. Synthetic Biology) - as of 2018^[2] 

The following section further examines the barriers to bioweapons within each stage of the pathogen synthesis process, and the (potential) affordances of synthetic biology which could enable malicious actors to surmount these barriers. The aim is to assess the level of expertise required to clear each stage, and whether synthetic biology would lower the barriers sufficiently for amateurs to do weaponize pathogens.

The main biotechnologies of concern in the near future (over the course of the next decade or so) are projected to be oligonucleotide synthesis, DNA assembly (assembling multiple smaller fragments of oligonucleotides into the desired larger sequence), and genetic modification (editing, deleting, and inserting desired sequences into targeted sites of a genome).^[8]

DISCLAIMER: In view of the information hazards involved, readers are strongly discouraged from speculating publicly about novel ways to cause harm with biology, be it in the comments below or in your own threat assessments. Therefore, even as I recognize that convergent technologies could contribute significantly to the biosecurity risks, I have deliberately redacted several points on how various non-biological technologies (e.g. AI) might be used to circumvent barriers at each of these stages.

Design & testing

Design and testing is not required if the malicious actor intends to use one of the known pathogens. Engineering known viruses to become more contagious, deadly or immune to antivirals remains extremely challenging, essentially requiring a great deal of trial-and-error by experts. However, scientific and technological advances in the near future could make this more accessible to less sophisticated actors.

• The modification of viruses to gain functions is very challenging due to limited knowledge of how genotype changes would translate to phenotype changes (and even further, predicting how such changes would manifest as disease in humans). Such modifications also often result in attenuation (i.e. less pathogenic) of the virus.^[2]
• Nevertheless, it is still feasible for sophisticated actors to do so through repeated trial-and-error e.g. In 2001, scientists successfully engineered mousepox to be lethal to mice that have been immunized against ordinary mousepox; avian influenza had also been engineered to allow for airborne transmission between mammals.^[9] Testing and learning from the tests is usually a time intensive process which requires a great deal of expertise and experience. 
• Publicized gain-of-function research, or progress in genotype-phenotype understanding may make such modified designs more accessible to less sophisticated actors. Malicious actors could also take advantage of automation tools (e.g.microfluidics, mass spectrometry, machine learning) to enable high throughput testing of agents.^[10] 
• Designing and synthesizing novel viruses from scratch is not very feasible with current technologies.

Production

Small-scale production and delivery could be sufficient for spreading contagious pathogens. The barriers seem high enough to prevent amateurs working from home from producing known pathogens even at a small scale, but graduate-level individuals may have sufficient expertise and equipment to do so.

• Large scale production is extremely challenging for non state-led/sponsored actors (see section on Aum Shinrikyo’s attempt above) because many agents lose infectivity or other features during scale-up.
• However, the small-scale production of most known viruses could be achievable with commercial mail-ordered oglios (fragments of the full virus RNA/DNA), by a graduate-level individual with relatively common cell culture and virus purification skills and access to basic (graduate-level) laboratory equipment. Such efforts would feasible with a relatively small organizational footprint (including, e.g., a biosafety cabinet, a cell culture incubator, centrifuge, and commonly available small equipment).^[2] 
• For instance in 2016, virologist David Evans led a team of experts to synthesize the horsepox (a close relative of smallpox) virus by using synthetic oglios mail ordered from a commercial company.^[11] While that company had processes to guard against abuse by terrorists, not all companies would have similar safeguards. Screening for oglios/segments of concern is currently not mandated for all gene synthesis companies.
• That said, virus synthesis is still far from being accessible to amateurs working from home. It still requires specialist expertise, experience and equipment. Specialised knowledge is difficult to acquire because much of it is tacit, local and collective in nature.^[12]

Stability and Delivery

Since infectious pathogens could be delivered at small scales, much of the challenges of stability and delivery that have held back Aum Shinrikyo’s bioweapons programme may not apply if contagious pathogens were used.

• Larger-scale attacks typically involve some form of aerosol dispersal, such as via a spray or an explosion are quite challenging to execute. They may require that the agent not only be prepared at the optimal particle size (between 1 and 5 micrometers) for inhalation but be concentrated enough, able to withstand freeze drying, suspension in aerosol preparations, packaging processes, long-term storage, and adverse environmental conditions such as ultraviolet sunlight or extreme temperatures.^[13] 
• Engineering the virus (see sub-section above on ‘design and testing’) could potentially increase its environmental stability but maintaining viability throughout the weaponization process is still likely to present a significant challenge, particularly for large-scale attacks. 
• However, using contagious pathogens could circumvent much of the challenges of scaling-up and delivery. Infectious agents could be delivered at smaller scales at multiple locations and allowed to spread on its own. At smaller scales, delivering a bioweapon can be as simple as contaminating food or water, sticking victims with a needle, or even smearing the agent on victims’ skin.^[14] There had already been precedented uses of bioweapons for assassination (e.g. case of Kim Jong-Nam). Some actors may even be able to find volunteers willing to spread infection by becoming infected themselves, akin to suicide bombers. 

Conclusion 

If my assessment is correct, it is quite concerning that at present there are likely to be States, Insider Lone Scientists and State-Sponsored terrorist groups/individuals that have both the capabilities and intention the capabilities to successfully start a pandemic with known pathogens.^[6] The main barriers for non-state-sponsored/ supported actors seem to only be: access to university-level lab equipment while being able to do such work undetected, and the screening by gene synthesis companies. The lack of appropriate screening regulations, publication of new pandemic-capable viruses online, and the availability of tabletop DNA synthesis machines could therefore pose significant risks. While non-engineered pathogens are quite unlikely to pose an existential risk for humanity, they could still have potentially catastrophic impacts amounting to tens of millions of lives, and much more suffering e.g. COVID-19, Spanish Flu.

What might be even more concerning in the near future are pandemics engineered with increased virulence, transmissibility, antiviral immunity and environmental stability. At present, the barriers to engineering a pathogen still seem quite insurmountable unless the bioweapons programme is a multi-year state-led/state-sponsored one. Only state actors would probably be able to do so reliably at present, and there are significant barriers deterring state actors who wish to remain in the international system from deploying such weapons. I would revise this likelihood upwards if Russia is further excluded from the international system.

However, developments in understanding of genotype-phenotype relationships through gain-of-function research and development of high-throughput automation of testing processes, could lower the barriers for engineering pandemics quite significantly in the coming years. Without regulatory intervention, these scientific and technological developments are likely to continue to advance rapidly. Designing and synthesizing a novel virus from scratch is currently (as of 2018) not very feasible. However, the outcomes can potentially be much more catastrophic than the weaponization of existing viruses (perhaps just as catastrophic as modifying existing viruses).

Acknowledgements

I deeply appreciate the comments and patient guidance from Chris Bakerlee, Tessa Alexanian and Ryan Teo, especially regarding the potential info hazards of this piece. All mistakes and ultimate decision on the risk-benefit tradeoffs are my own.

Annex - Assessment of Info Hazards

Potency of Information: Depends on factors such as how many people the information may affect, how intensely each affected person would be affected, how long the effects would last, and so on.

Assessment: 

• While I do not expect the readership to be very high (perhaps 30, if I am lucky), the article suggests some abstract/strategic ideas about how to design a bioweapon to cause maximum catastrophe (e.g. using contagious pathogens).
• Of concern may be that this post prompts others to run their own personal threat assessment exercises (either directly in the comments or through posts of their own), that suggest novel ways of using biology to do harm.  

Counterfactual rarity: refers to the number of people who are likely to have already developed or learned this information (or similar information), or to develop or learn this information soon anyway.

Assessment: 

• Most of the ideas are not new and are likely to be obvious for any trained synthetic biologist/life scientist. Many of the ideas here have also been made by other authors which I draw on, and the original articles are publicly available. 
• Nevertheless, this article does pull together relevant research from various open-sources and provides a framework that may help malicious actors to make sense of how (at a very abstract level) developments in synthetic biology might be applied to bioweapons development. 

References

1. ^{^}

   Eukaryote, 2019. The Germy Paradox - The empty sky: How close did we get to BW usage?

2. ^{^}

   National Academies of Sciences, Engineering, and Medicine 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. https://doi.org/10.17226/24890.

3. ^{^}

   V. Barras and G. Greub, “History of Biological Warfare and Bioterrorism,” Clinical Microbiology and Infection, 20 no. 6, (June 2014), 497–502,  Federal Bureau of Investigation 

4. ^{^}

   Richard Danzig, Marc Sageman, Terrance Leighton, Lloyd Hough, Hidemi Yuki, Rui Kotani and Zachary M. Hosford (2011). Aum Shinrikyo: Insights Into How Terrorists Develop Biological and Chemical Weapons. Center for a New American Security. 

5. ^{^}

   Zachary Kallenborn and Philipp C. Bleek, “Avatars of the Earth: Radical Environmentalism and Chemical, Biological, Radiological, and Nuclear (CBRN) Weapons,” Studies in Conflict & Terrorism 43:5 (2020): pp. 351381; Gary Ackerman, “Beyond Arson? A Threat Assessment of the Earth Liberation Front,” Terrorism and Political Violence 15:4 (2004): pp. 143170.

6. ^{^}

   Gary A. Ackerman, Zachery Kallenborn, and Philipp C. Bleek, 2022. Going Viral? Implications of COVID-19 for Bioterrorism. CTCSentinel Special Issue: The Biological Threat - Part Two. 

7. ^{^}

   Sonia Ben Ouagrham, 2014. Barriers to Bioweapons. Cornell Press. 

8. ^{^}

   Trump, B.D., Florin, MV., Perkins, E., Linkov, I. (2021). Biosecurity for Synthetic Biology and Emerging Biotechnologies: Critical Challenges for Governance. In: Trump, B.D., Florin, MV., Perkins, E., Linkov, I. (eds) Emerging Threats of Synthetic Biology and Biotechnology. NATO Science for Peace and Security Series C: Environmental Security. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-2086-9_1

9. ^{^}

   Linster M, van Boheemen S, de Graaf M, Schrauwen EJA, Lexmond P, Mänz B, Bestebroer TM, Baumann J, van Riel D, Rimmelzwaan GF, Osterhaus ADME, Matrosovich M, Fouchier RAM, Herfst S. (2014). Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus. 157(2):329-339. 

10. ^{^}

    Justine Calma, “AI Suggested 40,000 new possible chemical Weapons in just Six Hours,” Verge, March 17, 2022.

11. ^{^}

    How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA | Science | AAAS

12. ^{^}

    Tumpey TM, Basler CF, Aguilar PV, Zeng H, Solórzano A, Swayne DE, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science (2005) 310:77–80. doi:10.1126/science.1119392; Noyce et al. 2018

13. ^{^}

    Frerichs, R.L., R.M. Salerno, K.M. Vogel, N.B. Barnett, J. Gaudioso, L.T. Hickok, D. Estes, and D.F. Jung. 2004. Historical Precedence and Technical Requirements of Biological Weapons Use: A Threat Assessment. SAND2004-1854. Albuquerque, NM: Sandia National Laboratories.

14. ^{^}

    CBC. 2017. Women accused of poisoning North Korea’s Kim Jong-nam arrive at Malaysia court. CBC News: July 27.