Biological warfare: the history of microbial pathogens, biotoxins and emerging threats

Biological weapons are defined as a biological agent (such as a pathogenic organism or toxin) that produces effects through proliferation within or intoxication of a target host with the intent to incapacitate, harm or kill¹. Many pathogens have the potential to be a biological weapon. However, most experts believe Bacillus anthracis (anthrax), Variola spp. (smallpox), Yersinia pestis (plague), Clostridium botulinum (botulism) and Francisella tularensis (tularaemia) are the most likely agents to be employed in an act of warfare as they hold the most dangerous potential in their effect (Table 1)⁴. Characteristics of an effective biowarfare agent include their availability, virulence, degree of expertise required for weapons production, and the subsequent ease of dispersion (Figure 1)^2,5.

Table 1.  Biological organisms and toxins of relevance to biological warfare.

Figure 1.  Common characteristics of biological agents that influence their potential as weapons.

While rare, the deliberate use of biological weapons with the intent of causing mass terror and significant harm has a long history well before microbial pathogenesis was understood. Historically, past usage of biological warfare was predominantly characterised by the weaponisation of pathogens for sabotage, whereas the form of biological warfare most feared today is its use as a method of mass destruction, inflicting catastrophic devastation and loss through mass hysteria and subsequent economic damage⁶. Due to the increased threat of bioterrorism, it is crucial to understand the historical application of pathogenic organisms to evaluate the potential use of biological weapons in the future⁷.

Biological warfare during the past millennium can be divided into three main eras: (1) prior to the germ theory (up until the late 19th century); (2) the emergence of microbiology (late 19th century–1945); and (3) the modern era of molecular and reconstructed organisms (1945–present) (Figure 2)⁷. However, the historical study of biowarfare is problematic, and any conclusions must be treated with caution due to:

Figure 2.  Examples of biological warfare during the past 1000 years. (a) Depiction of a citadel siege where a tactic of ancient biowarfare was to catapult plague-infected bodies into the city by Rashid-al-Din (https://commons.wikimedia.org/wiki/File:Mongol_siege_Jami_al-Tawarikh_Edinburgh.jpg)/licensed under Public Domain. (b) Unit 731 personnel during WWII (November 1940) conduct a bacteriological trial upon a test subject in China by Unit 731 (https://sl.wikipedia.org/wiki/Slika:Unit_731_victim.jpg) =/licensed under Public domain. (c) Two R-400A bombs at an Iraqi military airbase with markings indicating they were intended to be filled with botulinum toxin by FAS (https://fas.org/irp/cia/product/Iraq_Oct_2002.htm)/licensed under Public domain. (d) The anthrax-laced letters addressed to Senator Daschle and Senator Leahy in November 2001 by Mirror Vax (https://en.wikipedia.org/wiki/2001_anthrax_attacks)/licensed under Public Domain.

• the lack of reliable microbiological and epidemiological data surrounding the alleged attacks;

• difficulties discerning a biological attack from a naturally occurring disease outbreak;

• secrecy surrounding biowarfare programs;

• the deliberate use of allegations for propaganda and hoaxes; and

• potential discord due to modern misinterpretation of ancient accounts.

It was not until major wars of the 19th century that science was harnessed in earnest for the application of biowarfare (Table 2). During the Cold War, the Soviet Union (USSR) had the most extensive and sophisticated covert biological weapons program ever developed by a nation⁸. Despite this, with the exception of the Japanese field trials (involving the release of infected fleas from aircrafts over Chinese cities to initiate plague epidemics) and intentional use of biological agents (anthrax) by Rhodesian troops, there are no well-documented biological attacks by nation-states⁹. A defining step in the modern era of biological warfare occurred after World War II, when individuals, small groups of activists and non-state parties gained access to potentially dangerous organisms to inflict harm on a wider population³.

Table 2.  History of biological warfare and bioterror attacks during the past millennium.

In life sciences, the dual-use dilemma describes scenarios where materials, equipment and scientific research can be used for both peaceful and malicious purposes¹⁰. Rapid advancements in biotechnology has extended the use of dual-use technologies to a growing number of individuals and organisations, making external monitoring and verification of dual-use sciences nearly impossible. The primary concern of dual-use research is the deliberate misapplication of biological sciences to cause significant harm to public health and safety¹¹. Alarmingly, very few pathways differentiate developing biological weapons to developing a vaccine, until there is the resolve to inflict injury (Figure 3)¹².

Figure 3.  Dual-use nature of biological agents and technology.

For example, in 2002, researchers artificially synthesised a ‘live’ polio virus with blocks of DNA purchased via mail-order to emphasise the ease in which terrorists could produce biological weapons¹³. In 2012, researchers genetically modified the bird flu virus H5N1 to become airborne and easily transmissible among ferrets, presenting the risk that a human-transmissible strain of H5N1 could kill millions of people if produced. Controversial cases like this have led parts of the scientific community calling for greater caution and government regulations to prevent the misuse of biological research. For example, in November 2012 the Defence Trade Control Act 2012 was established to control the transfer of military and dual-use goods and technology to ensure the export of such sensitive technologies are consistent with Australia’s security interests and international obligations.

Public Health is defined as the science of preventing disease, prolonging life and promoting health through organised efforts of society¹⁴. Although the probability of an attack is difficult to predict, bioterrorism is not a hypothetical threat and presents a significant challenge for public health. Critical factors that may influence the magnitude of a public health emergency include:

• terrorist intent;

• the destructive power of a biological agent; and

• society’s vulnerability to many biological agents.

A successful assault could initiate epidemics of some magnitude, and with a degree of lethality unprecedented in modern history¹. Unlike conventional terrorist acts which can be readily identified and limited to a specific geological region, a covert biological attack could remain undetected for an extended period of time, be widely spread depending on the pathogenicity of the organism, and may not be immediately recognised as a deliberate attack¹⁵.

Most procedures developed to respond to a bioterror act are the same as those necessary to respond to natural outbreaks of infectious diseases in the environment including early detection, a comprehensive investigation and an effective response. Intensive international cooperation, government preparedness and medical defence against pathogenic organisms must be a central pillar of safeguarding national security, where the ultimate goal is to prevent suffering and loss of life¹⁶. In addition, to improve biosecurity for both natural epidemics and intentional attacks, international cooperation should include joint biopreparedness exercises involving various countries to develop necessary skills and systems to deal with unexpected outbreaks of disease. Command, control and coordination of multi-agency operations at federal, state and city locations will ensure:

• hospitals are equipped to deal with the sudden influx of patients;

• rapid diagnoses can be made;

• stockpiles of critical supplies including vaccines, antimicrobials and equipment are rapidly dispatched; and

• sufficient emergency personnel can be swiftly deployed.

Syndromic surveillance is an integral component of biopreparedness that uses the acquisition of automated data to monitor individual and population health indicators in real-time¹⁷. The primary aim of syndromic systems is to identify illness clusters, focussing on the early symptoms (prodrome) period before confirmed diagnoses are reported in order to mobilise a rapid response and reduce the potential burden of disease¹⁸. Syndromic surveillance primarily measures the incidence of clinical symptoms reported; however, it also utilises other data sources such as emergency department patient volume, emergency calls, unexplained deaths, insurance claims, clinical laboratory ordering volumes, school/work absenteeism, over-the-counter pharmaceutical sales and increases in internet-based health inquires¹⁸. For example, if a bioterrorist act involved the deliberate release of Yersinia pestis, a syndromic surveillance system might detect an influx in the number of influenza-like illnesses and thus act as an early warning tool of a covert biological attack. Real-time analyses of relevant data make syndromic surveillance valuable for the rapid detection, monitoring and investigation of bioterrorist-related disease outbreaks¹⁹.

The 1975 Biological and Toxin Weapons Convention (BTWC) was the first multilateral disarmament treaty banning the development, production and stockpiling of bacterial and toxin weapons of mass destruction²⁰. Although the BTWC has 187 State-Parties and Signatory States, history tells us that virtually no country with the means to develop weapons of mass destruction of any nature has refrained from doing so³. The 1979 accidental anthrax outbreak in Sverdlovsk (USSR), and the 1990–1991 discovery of the Iraqi biological warfare program during the Persian Gulf War (Table 2) highlight that international treaties like the BTWC are ineffective in the absence of operative inspection provisions. There has been some criticism that a central flaw of the treaty is that there are no references to the world of research, or any references to what may be considered offensive or defensive activities in an investigative context that prohibits nations from conducting, assisting or authorising research aimed at biological warfare^8,20. There is an immediate need for formal measures and enforcement protocols to ensure compliance and prevent systematic violations of the convention.

Perhaps the most dangerous threat using biological warfare is the application of genetic engineering to influence the pathogenicity and capacity of biological agents to be used as weapons²¹. Synthetic biology is an evolving interdisciplinary field in which engineering principles are applied to biology²². Although the knowledge gained from synthetic biology is not a direct threat to biosecurity, risks associated with the potential exploitation of this technology have emerged in recent years.

During the eighth review of the BTWC in 2016, it was acknowledged that advances in synthetic biology had expedited the development of biological weapons²². Although some effort is being made to put in place global safeguards, there is no regulated plan to deal with the threat of a bioterror attack, including the exploitation of synthetic biology. A key challenge is how to establish standards, policies and regulations without restricting the continued growth of biotechnology. To mitigate potential harm, scientists should play an integral role in the strategic and systematic collaboration between public health, intelligence communities and national security to ensure a coordinated defence against the misuse of synthetic biotechnology. As part of Australia’s biosecurity efforts, the Security Sensitive Biological Agents (SSBA) Regulatory Scheme was developed to regulate the handling of harmful biological agents on the list of SSBAs. The scheme aims to limit the opportunities available for deliberate acts of bioterrorism to occur and provides a legislative framework for the control and handling of SSBAs.

For centuries, biological agents have been used for warfare or terrorist activities by governments, non-state organisations and individuals. The threat of a biological attack remains a serious concern for local and international security. Although the state of biopreparedness is improving, many important challenges concerning the consequences of a biological attack remain. Governments must be flexible with the ability to adapt to changes in the global security environment, and all countries must strive to make a coordinated effort to develop appropriate policies, operations and preventive countermeasures for possible future attacks.

The authors declare no conflicts of interest.