DARPA’s Prepare program: Preparing for what?

By Filippa Lentzos, Jez Littlewood | July 26, 2018

The US military—specifically, the Defense Advanced Research Projects Agency, or DARPA—announced plans in May to initiate a “gene tuning” program. Called “Prepare” (short for “Pre-emptive Expression of Protective Alleles and Response Elements”), the program aims to develop programmable modulators that temporarily boost protective genes, either before or after exposure, to biological, chemical, or radiological health threats. Inadvertently, however, the project may contribute to rising international tensions in the biological field. The program might push the limits of what is allowable under international security treaties, particularly the 1972 Biological and Toxin Weapons Convention (BTWC).

The United States, as the keeper of the largest biodefense enterprise in the world, has a special responsibility to demonstrate its compliance with the multilateral anti-bioweapons regime, whose foundation is the BTWC. Washington also has a security interest in demonstrating compliance. The United States must be sensitive to the way its biodefense activities may be perceived externally—that is, in its strategy for defending against bioweapons, the United States must factor in the role that mistrust can play in others’ attitudes and behaviors, as well as the role that its own actions can play in provoking that mistrust. It is not enough, therefore, for the United States to be self-confident about its treaty compliance; to avoid arousing international suspicion, it must proactively de-escalate threat perceptions associated with its biodefense activities.

Expansion of “gray zone” biodefense. Today, concerns about biological weapons do not simply involve possession or non-possession of “weapons.” Indeed, few analysts believe that any country is secretly stashing away weaponized pathogens, ready for launch. Instead, concerns primarily involve the degree to which states have the capacity and intent to threaten or perpetrate a biological attack. Capacity to perpetrate an attack is widespread, given the ubiquity of biotechnology. But intentions can be opaque. Security concerns therefore focus on dual-use equipment, processes, and know-how. Such concerns are particularly acute where biodefense programs are concerned.

Much biodefense work is justifiable. Such work includes development of protective masks and clothing, air and water filtration systems, detection and identification devices, and decontamination systems. Some activities, however, fall into the gray area between defensive and offensive work—the area where perceptions may differ regarding what qualifies as defensive or offensive. Activities of most concern have traditionally been those related to “threat assessment,” an area in which possible offensive applications of pathogens are investigated as a way to develop defenses and determine appropriate countermeasures.

The US National Biodefense Analysis and Countermeasures Center has been particularly controversial. The center, established following the September 11 and anthrax attacks, is intended to prevent technological surprise. It works toward this goal by pursuing capabilities within pathogenesis, genetic engineering, genomics, bioregulators, and immunomodulators. It also investigates novel delivery of threats, novel packaging, and aerosol dynamics. The language used by the center’s deputy director to describe its work on pathogens—“acquire, grow, modify, store, stabilize, package, disperse”—is uncomfortably close to language that might describe the activities of an offensive bioweapons program.

The center’s activities could create the impression that, though the United States might be conducting biodefense activities to more fully understand the nature of hypothetical threats, it could just as easily carry out such activities to gain the ability to threaten or perpetrate a biological attack. And when the center’s activities are coupled with the US Army’s Whole System Live Agent Test Chamber facility at the Dugway Proving Ground in Utah—where experimenters can control temperature, relative humidity, and wind speed to simulate a range of climatic conditions in which pathogens might be released—the international community harbors understandable concerns over the growing, technologically sophisticated, and increasingly secret US biodefense enterprise.

The center and the Dugway test chamber form the backdrop for the four-year Prepare program. The program seeks to leverage insights from emerging gene-editing and genome engineering technologies but—as highlighted in the program’s press release—it takes a new approach. Much recent research has investigated the permanent modification of genomes, achieved either by cutting DNA and inserting new genes or by changing the underlying sequence to change the genetic code. The Prepare program, on the other hand, focuses on temporarily modulating gene activity via the cellular messages that carry out DNA’s genetic instructions inside cells: the epigenome, transcriptome, and epitranscriptome. The program, inspired by advances in understanding when and how genes express their traits, intends to “identify the specific gene targets that can confer protection, develop in vivo technologies for programmable modulation of those gene targets, and formulate cell- or tissue-specific delivery mechanisms to direct programmable gene modulators to the appropriate places in the body.”

Significant questions surround the scientific feasibility of the program and the way in which gene tuning would work in practice. The program also raises considerable health, safety, and environmental concerns. Of particular concern to this article’s authors, however, are the program’s implications for international security in the current geopolitical climate. The Prepare program strives to gain knowledge and develop technological capabilities that would protect warfighters, first responders, and civilian populations and lead to greater public-health preparedness for major incidents. But it would also, inevitably, entail greater awareness of populations’ vulnerabilities and provide greater understanding of how to deliver programmable gene modulators to reduce protections (that is, to lower the human body’s natural defense).

How to communicate intent. The Prepare program continues to expand US biodefense gray-zone activities—and states keeping a close eye on the US biodefense enterprise may well question the program’s intent. Some might feel threatened by it. A small number—concerned about new threats highlighted by US activities, or in preparation for a sudden change in the US attitude toward the absolute prohibition of biological weapons—might even take reciprocal action, initiating additional gray-zone biodefense activities of their own. The result could be a downward security spiral in which greater offensive know-how on all sides leads to increased danger of biological attack against more states.

Decades ago, the international relations scholar John Herz defined what is now known as a security dilemma—a situation in which efforts to improve security run the risk of achieving the opposite. Herz’s words are particularly poignant in the biodefense context: “Mutual fear of what initially may never have existed may subsequently bring about exactly that which is feared most.” The proliferation of increasingly sophisticated biodefense capacities, within and among states, can cause nations to doubt one another’s intentions. Such doubts might potentially result in bioweapons capabilities and, ultimately, bioweapons use.

Nations’ intent regarding biological programs may ultimately be unknowable. Still, there are degrees of ignorance. The international community should work toward two aims: First, to reverse governments’ tendency to assume that security is enhanced by secrecy and, second, to significantly enhance nations’ transparency and their communication of intent. A good opportunity to bring these issues into discussions of international security policy will come during the fourth intersessional work program of the BTWC, which begins next month.

For projects or programs with high potential for misuse, such as Prepare, efforts must be made to proactively disclose information and to communicate intent. Issuing public calls for proposals, awarding contracts to nongovernmental entities, and issuing press releases all help to some degree, but on their own are insufficient. The BTWC provides a useful forum for presenting dual-use disclosures to the international community and for facilitating discussion about potential misunderstandings, ambiguities, and misperceptions among allies and adversaries. No perfect institutional mechanism for such interactions exists within or under the BTWC at this juncture, but state parties can use and enhance some existing means over the coming years.

One place to start is with the compliance reports that any state party may submit prior to treaty review conferences. Building on that foundation, states could engage independent experts to conduct additional, annual compliance reviews focused specifically on their biodefense activities, with the reviews explicitly describing how their compliance judgments are reached. Some countries already do something similar. Canada, for instance, publishes annual reports by a Biological and Chemical Defence Review Committee, composed of three nongovernmental scientists. The committee was established in 1990 to assure “the Canadian public, as well as the international community… that the Government’s policy of maintaining only a defensive capability in this field is fully respected at all times.”

A second approach would be to encourage national endorsements of, and increased participation in, the ad hoc peer reviews between national biodefense programs that have been initiated recently. Over the last five years, a small number of states have invited peers from other nations to visit their facilities and informally review their treaty compliance. Some of these initiatives have involved visits to biodefense facilities. Some have also been opened to civil society participation, allowing information about the peer review exercises to be brought into the public sphere.

A reinvigorated and expanded confidence-building process could form a third approach to enhancing international communication regarding biodefense activities whose potential for misuse is high. Confidence-building measures constitute the main formal mechanism whereby BTWC member states, on an annual basis, exchange information about their programs. The habit of disclosure sets up expectations of openness, normalizes oversight, and in general makes for a less dangerous condition of uncertainty. Confidence-building measures under the BTWC involve requests for information on the objectives and funding of biodefense programs; principal research and development activities; facilities involved; the organizational structure and reporting relationships of the facilities; and details about any sub-contracted parties from industry, academia, or other non-defense institutions. Such confidence-building measures also provide states with an opportunity to provide rationales and justifications for their biodefense activities. The United States, alongside 30 other states, makes its confidence-building measures publicly available; more than 40 states still restrict access to their submissions.

Yet little is known about individual states’ interpretations and use of information derived from confidence-building measures. Likewise, little is known about the extent to which states feel that confidence-building measures provide necessary transparency and actually build confidence. Under certain circumstances, inadequate interaction and discussion regarding the information exchanged via confidence-building measures could prove detrimental to confidence in compliance—that is, misplaced or ambiguous information in a confidence-building measure could be wrongly interpreted, even if it did not necessarily correspond with a deliberate effort to “cheat.” In fact, there may be reasonable explanations for indicators that hint at non-compliance. However, in order for such explanations to be sought and presented, a safe space in which to ask questions must be established.

One option could be an interactive “public peer review” of confidence-building submissions. Through a public peer review, states could demonstrate responsible biodefense—while exchanging experiences and best practices with government and civil society peers regarding the collection, collation, interpretation, and analysis of data from confidence-building measures. Such a forum could normalize a process in which biodefense activities are questioned and clarifications are sought. A process of this sort could significantly enhance the value of confidence-building measures.

Policy development cycles for BTWC review conferences entail a two-year process for considering the advantages and disadvantages of different courses of action. Proposals for the review conference in 2021 will need to be in the public domain at the beginning of that year so that states and actors can consider, review, and comment upon them—if the review conference is to make strides in the right direction. The complexities of communicating intent, however, are such that proposals from a nation such as the United States will involve intensive consultations with stakeholders (as well as consultations within the inter-agency process) in the preceding year (2020). As a result, proposals would need to be formulated throughout 2019. As one of the pre-eminent champions of the Biological and Toxin Weapons Convention, the United States must lead from the front. It has little time to lose.


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Keywords: DARPA, gene tuning
Topics: Biosecurity

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