Improving the Select Agent Program

Immediately following the 2001 anthrax attacks, U.S. officials didn’t know how many U.S. research laboratories held stocks of Bacillus anthracis, the causative agent of anthrax disease. And they didn’t know how many researchers within those labs that did have stocks had ready access to the strains. This complicated the investigation of the source of the material used in the attacks. In the seven intervening years, U.S. officials have improved this situation. As a consequence of an expanded Select Agent Program, they now monitor the possession and transfer of more than 70 viruses, bacteria, toxins, and rickettsia (including anthrax) that could theoretically be processed into bioweapons, in all U.S. government, academic, and private laboratories. By law, only individuals cleared by the Department of Justice have access to these “select” biological agents.

This increased accountability and security for pathogens is valuable, especially in light of FBI assertions that the anthrax used in 2001 came from a U.S. biodefense laboratory. However, the security benefits of tracking pathogens are inherently limited, and the Select Agent Program may also inadvertently and negatively affect the progress of scientific research and international scientific collaborations. As the U.S. Congress considers legislation to reauthorize the Select Agent Program, it should take steps to evaluate and fine-tune the program to provide maximum benefits to security while promoting scientific advances. Research on pathogens certainly present risks, but the greater risk is in not pursuing the research, and failing to develop effective vaccines and medicines to prevent and treat disease.

The program’s origins

The Select Agent Program was launched by the Antiterrorism and Effective Death Penalty Act of 1996, which prohibited the transfer of some “select” agents from one laboratory to another without registration with the CDC. Congress passed the law in response to the difficulties in prosecuting Larry Wayne Harris, a member of the white supremacist group Aryan Nations, who in 1995 legally obtained Yersinia pestis, the causative agent of plague, from American Type Culture Collection, a biological services company. The 2001 USA PATRIOT Act and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 strengthened accountability and restrictions for access to agents on the select agent list.

The program primarily involves three government agencies: the Animal and Plant Health Inspection Service (APHIS) at the Department of Agriculture, the Centers for Disease Control and Prevention (CDC) at the Department of Health and Human Services; and the Department of Justice. The CDC regulates some select agents, such as Ebola virus, and APHIS is the sole regulator of others, such as Foot and Mouth virus. Some agents, such as anthrax, are “overlap” agents, which can be regulated by either CDC or APHIS. These agencies also inspect the facilities where the select agents are researched.

As of April, 9,918 people were approved to work with select agents through CDC, and 4,336 through APHIS. As of May 2, 2008, 324 entities, including government agencies, academic institutions, corporations, societies, and sole proprietorships, were registered with the CDC select agent program. Though officials have strengthened pathogen security measures since 2001, a range of factors inherently limit the effectiveness of the Select Agent Program:

• The program is U.S. centered. It is a criminal offense in the United States to possess select agents, unless for bona fide medical, clinical, or research purposes, yet laboratories outside the United States are not governed by the same rules.
• Most select agents are naturally occurring. With the exception of the smallpox virus and the 1918 flu virus, all select agents can be found in nature, in hospital laboratories, or in sick people and animals. For example, Burkholderia pseudomallei, the causative agent of melioidosis, is endemic in Southeast Asia and Northern Australia; Viral Equine Encephalitis occasionally appears in Central and South America; plague bacteria is presently causing the collapse of prairie dog colonies in the western United States; and Bacillus anthracis is found in laboratories and soil all over the world.
• Tracking individual pathogens is extremely difficult. Living organisms grow and multiply. Miniscule amounts of a pathogen could be sufficient to produce tons of pathogenic cultures.
• New technologies can circumvent the need to acquire select agents from a laboratory. In 2002, researchers at SUNY Stony Brook reported that they constructed poliovirus from short laboratory-synthesized sequences of DNA.¹ Since then, DNA synthesis technologies have dramatically improved, and many more select agents are within reach of being synthetically created.
• New potential agents are not on the list. A recent report from the National Science Advisory Board for Biosecurity warns, “It is increasingly easy to produce synthetic genomes that encode novel and taxonomically unclassified agents with pathogenic properties equivalent to, or possibly more harmful than, current Select Agents.” In other words, advances in synthetic genomics and synthetic biology could lead to new pathogens that will not easily fit into an oversight framework.

In addition to these challenges, the Select Agent Program could present roadblocks in the event of a public health crisis. In 2004, a group of 13 scientists wrote a letter to the CDC asking that the SARS virus be kept off the select agent list because they feared that adding the virus to the list would hinder important research.² Indeed, placing the virus on the list would have caused research delays–researchers would have needed to be cleared by the Department of Justice, a process that takes about 45 days–in the midst of a public health crisis. Placing an agent on the select list requires some laboratories to make expensive security upgrades to protect the agent from theft, loss, or unauthorized access, and the facilities would need to be inspected by the CDC. Shipping restrictions for transferring samples from one laboratory to another could also interfere with international collaborations, and running afoul of the law could result in up to $250,000 in fines for an individual and $500,000 for a research institution for each select agent violation. Criminal penalties could include imprisonment for up to 5 years.

Observers blame the fear of violating the law for a decrease in the number of samples that clinical laboratories send to research universities.³ If scientists at a clinical laboratory identify a select agent, they have a week to transfer it or destroy it; too often, it is easier to destroy the sample than to fill out all the necessary forms and take the risk that criminal penalties could result from doing it improperly.

The importance of the research mission

The limitations of tracking pathogens suggest that the Select Agent Program can be only one part of U.S. biodefense efforts. Additional oversight and accountability measures may strengthen the Select Agent Program, but it will be important to balance gains in security with the need to pursue scientific advances that lead to the development of medical countermeasures against biological weapon threats. Legislation introduced in the 110th Congress, the Select Agent Program and Biosafety Improvement Act of 2008 (S. 3127 and H.R. 6671), asks the National Academy of Sciences to evaluate how the Select Agent Program has enhanced biosecurity and biosafety and what effect it has had on international scientific collaboration and scientific advances. This could be an excellent opportunity to evaluate how important research can proceed as securely as possible.

The FBI investigation into the 2001 anthrax letters suggests it is possible for one person to produce a lethal bioweapon without specific training and without specialized equipment. In the face of this security dilemma, it is imperative to develop new medical countermeasures such as vaccines and drugs, diagnostic tests, and cost-effective approaches to decontaminating physical structures. While restricting access to pathogens in laboratory stocks is important, any additional security for select agents needs to proceed with caution and knowledge of the program’s limitations in order to protect the research mission.

¹ J. Cello, A. V. Paul, and E. Wimmer, “Chemical Synthesis of Poliovirus cDNA: Generation of Infectious Virus in the Absence of Natural Template,” Science, vol. 297, no. 5583, pp. 1,016-1,018.
² M. Enserink, “Researchers Urge U.S. to Keep SARS Off Select Agent List,” Science, vol. 304, no. 5678, p. 1,726.
³ Dana Wilkie, “Select-Agent Security Clearance Stymies Research,” The Scientist, vol. 18, no. 10, May 24, 2004.