Arturo Casadevall and David A. Relman
Abstract | Anxiety about threats from the microbial world and about the deliberate misuse of microorganisms has led to efforts to define and control these dangers using lists and regulations. One list with tremendous legal implications and a potentially huge impact on research is the Select Agents and Toxins List, which was created by the US Government to limit the possession of and access to particular microorganisms and toxins. In this article, in addition to highlighting general problems with taxonomy-based, microorganism-centric lists, we discuss our view that such lists may have the paradoxical effect of increasing the societal vulnerability to biological attack and natural epidemics by interfering with the sharing of microbial samples and hindering research on vaccines and therapeutics.
Humankind has a delicate and intricate set of relationships with a microbial world of astonishing diversity. In recent times, these relationships have become increasingly strained, reflecting the emergence of new pathogens as agents of naturally occurring disease as well as the possibility that some microorganisms could be deliberately used to cause harm. Faced with this situation and the imperative of developing public-health countermeasures, it is a natural desire to begin to organize, categorize and prioritize these threats. A common feature of such efforts is the generation of a list, sometimes in rank-descending order on the basis of importance or some other metric. A list gives the appearance that one has bounded and specified an issue or problem and can suggest or define priorities. But lists are, by their nature, incomplete and, more impor- tantly, they can inappropriately limit creative or broad thinking as well as subtly mislead viewers into organizing their world view in
a narrow and biased manner. Today, research, resource investment
and public health strategies in microbiol- ogy and infectious diseases have been co-opted and commandeered to a degree that is unprecedented in history by a few lists, most notably by the Select Agents and Toxins List (SATL). The implications of this are potentially profound and not entirely beneficial. In this Science and Society article, we explore the ramifications of the SATL for microbiology and microbiologists. Our goal is to identify and discuss the positive and negative aspects of microbial threat lists and to provide recommendations for maximiz- ing the benefits and minimizing the detri- ments of such lists. Although we focus here on the SATL, the problems that we discuss are generic and pertain to all lists of biologi- cal agents and toxins that are created for the purposes of regulation and prioritization of resource allocation. Examples of other lists are the Australia Group List and the National Institute of Allergy and Infectious Diseases Category A, B, and C Priority Pathogens List.
The Select Agents and Toxins List
Beginning in the 1990s, laws and regula- tions to control the access to and the use of particular microorganisms and their products were formulated in the shadow of terrorist acts against the United States and other countries, with the goal of reduc- ing the risk to society of deliberate attacks with biological agents. These efforts were preceded by the Biological Weapons and Toxins Convention of 1972 that sought to achieve an international ban on the use of microorganisms and toxins in warfare. One result of those laws and regulations in the United States was the generation of a list of organisms that now carry the designa- tion ‘Select Agents and Toxins’ (for more information, see the National Select Agent Registry website). Other nations and inter- national organizations have carried out similar actions or have at least contemplated doing so. The current SATL is jointly admin- istered by the US Department of Health and Human Services and the US Department of Agriculture and contains approximately 80 microbial agents and toxins, defining them, de facto, by their taxonomic name.
The inclusion of a microorganism on the SATL imposes substantial regulatory restric- tions on the access to and possession and distribution of this organism1. For example, to work on microorganisms that are present on the SATL, institutions must register with the US Government, and individuals with access to these organisms must undergo background checks that can be highly intrusive and time consuming. A regula- tory framework is now in place that imposes strict protocols on how such microorganisms are accessed, transported, maintained and disposed of, with violations carrying consid- erable penalties. The inclusion of a micro- organism or toxin on the SATL is based on the consideration of several criteria, includ- ing its effect on human health, its contagion potential and the availability of vaccines and therapeutics. The SATL is reviewed regularly to include and exclude microorganisms and toxins on the basis of new developments.
Benefits and drawbacks
The laws and regulations that gave rise to the SATL were intended to provide a potential benefit to society by both restricting access to certain microorganisms and creating a legal infrastructure for the prosecution of individuals who are found to be in possession of these organisms without proper registra- tion. To fully appreciate the benefits and drawbacks of the SATL, it is important to note the distinction between biosafety and biosecurity. Biosafety is defined by the WHO as the containment principles, technologies and practices that are implemented to prevent unintentional exposure to pathogens and toxins or their accidental release2. By contrast, biosecurity is defined as the protec- tion, control and accountability for valuable biological materials (including information) in laboratories in order to prevent their unauthorized access, loss, theft, misuse, diversion or intentional release2. Although biosafety and biosecurity are related, and fre- quently confused by both the public and sci- entific community, these two terms differ in the crucial criterion of intent. In this regard, it is essential to note that the SATL is prima- rily an instrument of biosecurity. These laws bypass the thorny issue of intent by assum- ing that unregulated possession of these agents is in itself a threat to society regard- less of intended use, and they thus provide society with a powerful prosecutorial tool for law enforcement. It can be argued that the SATL-associated regulations also mitigate risk from biosafety concerns by imposing
a strict regulatory environment on labora- tories working with such microorganisms. However, in the United States, guidance for issues such as reducing the likelihood of accidents involving pathogenic micro- organisms and using the correct laboratory practices for handling microorganisms are derived from biosafety regulations3 that
do not have the regulatory authority of the SATL. Thus, the contribution of the SATL to public biosafety, if any, is modest and primarily limited to immediate laboratory personnel, as (with the exception of variola virus) many of the agents on the SATL, such as Bacillus anthracis, Coccidioides spp. and Francisella tularensis, are not contagious. For microorganisms that no longer circulate in the environment in a disease-causing form, such as variola virus, or that are difficult to obtain from natural sources, such as Ebola virus, the SATL makes an important poten- tial contribution to biosecurity by greatly restricting access to these agents.
For agents that can be recovered from the environment or endemic regions or that can be synthesized in the laboratory by individuals with microbiological knowledge, the possible contributions of the SATL to biosecurity are less obvious. The fact that the organisms in the US anthrax letters of 2001 presumably originated from a federal labora- tory facility4 has provided a powerful justi- fication for the oversight of laboratories that handle such agents. However, B. anthracis causes recurring outbreaks of veterinary anthrax in North America, where the organ- ism can be recovered from animal carcasses5. Similarly, Burkholderia pseudomallei, another bacterium on the SATL, can be readily recovered from the environment in endemic regions6. Hence, restricting access to such microorganisms through their inclusion on the SATL could reasonably be assumed to pose a hindrance to their acquisition for nefarious uses, but these regulations cannot be expected to stop determined individu- als from obtaining these organisms from environmental sources.
The security of society also requires a vigorous research enterprise, as knowledge is essential for defeating potential threats by the creation of diagnostics, vaccines and new therapies. In this regard, the SATL is a potential double-edged sword, and one can appreciate a paradoxical scenario in which the absence of these countermeasures increases the likelihood that an agent is included on the SATL, but such counter- measures may not be forthcoming if the reg- ulations interfere with the relevant medical research that is needed. The causative agent of soybean rust, Phakopsora pachyrhizi, was removed from the SATL for reasons that included the urgent need for timely research on effective means to manage this disease7; this effectively acknowledged the potential detrimental effect of the ‘Select Agent’ desig- nation on the research that is needed to con- trol such microorganisms. Furthermore, the cost to society of burdensome regulations could extend to work on health problems other than the intended diseases associated with the agents themselves. For example, some agents on the SATL, such as botulinum toxin, ricin and anthrax toxins, have thera- peutic uses in neurological disorders and cancer8. Regulations that inhibit research with certain microorganisms could reduce preparedness against future nefarious or natural outbreaks with that agent and could conceivably interfere with the development of therapies against other conditions that rely on products from such organisms.
Unfortunately, there are no good metrics with which to quantify work that is not car- ried out as a result of burdensome regulations, but it is reasonable to posit that as regulations proliferate so investigators who have a choice are more likely to work in less restricted areas of science. As choice in science is often a feature of academic and scientific success, the notion that some of our most capable sci- entists could opt to work in areas of research that have fewer burdensome regulations raises troubling issues for our future preparedness against biological weapons and certain emerging infectious diseases.
In short, the authors of this article, Dr. Casadevall and Dr. Relman, discus some of the implications of compiling and publishing lists of microorganisms and toxins which could potentially be used as biological weapons. On the one hand, they argue that by recognizing these toxins and microorganisms as potential threats to humanity, institutions such as the US Department of Health and Human Services have the means to safeguard people’s safety due to their restrictive and punitive policies on accessing and handling those agents. On the other hand they state that, for scientists, the difficult access to such agents hinders the purposes of scientific research to improve diagnostics, vaccines, and treatments for human health conditions that might or might not be directly related to toxins and microorganisms listed as potential bio threats.
I think the article offers a valid criticism regarding the offset of this particular kind of preventive measure against terrorism. First, if agents are included in microbial threat lists based on their effect on human health, its contagion potential, and the availability of vaccines and therapeutics, how can one decrease the likeness that some microbes and toxins might become potential threats if studies aimed to develop vaccine and improve therapeutics are discouraged? As far as we can see, policy has not been tailored to the needs of the general public and the scientific community refraining scientists from doing their work. Second, restricting access to stored biological agents does not prevent the individuals from synthesizing the same organisms or obtaining them from environmental sources. Such is the case of B. anthracis, which according to the article, this microorganism causes recurring outbreaks of veterinary anthrax in North America.
Overall, measures taken towards biosecurity should not be limited to grouping agents and toxins in microbial threat lists. Effective countermeasures against these selected pathogens should also be prioritized by developing antimicrobial drugs and vaccines and finding methods to restore or promote health across the globe at affordable rates, paying special attention to those who are immunocompromised individuals.