New review of anthrax case discussed by review committee vice chair, Stanford bioterrorism expert

- By Bruce Goldman

David Relman

David Relman

In 2001, a mystery perpetrator mailed a series of anthrax-laced letters to several locations, killing five people. In 2008, shortly after emerging as the prime suspect in an exhaustive investigation by the FBI, an Army microbiologist, Bruce Ivins, PhD, committed suicide. On Feb. 15, a National Academy of Sciences committee, charged in September 2008 with reviewing the scientific approaches used by the FBI in that investigation, released its report. The report said that the scientific evidence, while consistent with the law-enforcement findings, did not provide definitive proof linking anthrax in Ivins’ lab to the letters. David Relman, MD, vice chair of the review committee, is a professor of microbiology and immunology and of infectious diseases at the Stanford University School of Medicine. He answered the questions below from Bruce Goldman, a science writer in the medical school’s communications office.

Q: Did your review uphold the FBI’s findings? Is this case still open?

Relman:The main conclusion by the FBI and Department of Justice of their scientific investigation was that the Bacillus anthracis in the letters was derived from a flask called RMR-1029, which was located in the lab of Dr. Bruce Ivins at the U.S. Army Medical Research Institute for Infectious Disease in Frederick, Md.

We found that the FBI did a lot of things well — they reached out to some of the best scientists in the world, they executed a variety of scientific procedures in a very capable fashion, they helped to promote the nascent field of microbial forensics, and they dedicated considerable resources towards these goals.

However, we also found some problems and gaps in the scientific investigation. Although the scientific evidence was supportive of a link between the letters and that flask, it did not definitively demonstrate such a relationship, for at least two reasons.

First, the FBI was looking to match the anthrax strain in the letters to what existed in labs. But large-scale production of anthrax spores encourages the emergence of just the kind of mutant strains that were found in the anthrax letters. Since labs tend to save original isolates and may not save samples of large-scale production runs, it’s possible that the samples gathered by the FBI missed mutants that arose during such runs. This possibility was not given adequate consideration.

Second, the FBI still might not have found other matches, because there’s no guarantee that the bureau had assembled a comprehensive library of lab strains: The repository of anthrax samples that the FBI created for comparison with the anthrax in the letters may not have been representative of all relevant anthrax stocks around the world. The newly revealed, but inconclusive, information about possible B. anthracis Ames at an al Qaeda overseas location highlights this issue. In addition, the instructions in the subpoena the FBI sent to scientists known to be in possession of the B. anthracis Ames strain lacked specificity, so there’s no certainty that scientists who were subpoenaed submitted samples of all the mutant strains in their possession. In light of these and other problems and gaps in the science performed as part of this investigation, our overarching finding was that it is not possible to reach a definitive conclusion about the origins of the B. anthracis in the mailings based on the available scientific evidence alone.

We were not asked, nor properly constituted as a committee, to judge the conduct of the law enforcement inquiry. In February 2010, the Justice Department closed its investigation of the anthrax mailings, concluding that Dr. Ivins had committed the attacks.

Q: Where did your own particular area of expertise get put into play in this review?

Relman: I have expertise in several relevant areas, including microbiology, microbial genomics and biological terrorism. Microbial genomics played a disproportionately important role in the scientific investigation because of the early realization that the genetic fingerprints of the strains in the spore-containing letters might provide a lead to the spores’ source.

Q: As I understand it, anthrax is a disease not uncommon among animals, such as cattle. Does the organism responsible for anthrax have to be substantially modified to become a bioterror weapon directed at humans?

Relman: Anthrax is generally a disease of herbivores (e.g., cattle, sheep, horses), which acquire the infection by grazing on contaminated soil. The disease is not contagious. Anthrax spores are highly resistant to environmental insults and allow the bacterium to survive for long periods in soil. The course and outcome of human anthrax depend on dose and on whether the infection is acquired via the skin, gastrointestinal tract or inhalation, which is the most lethal manifestation. B. anthracis spores can be produced in prodigious quantities in a form that is readily aerosolized and inhaled. Preparation and production of spores suitable for use as a weapon does not require unusual skills, equipment or reagents.

Q: What made this case, and the FBI’s investigation of it, so challenging?

Relman: After the tragic mailings of letters containing B. anthracis in 2001, the FBI began an extensive investigation involving many experts and tremendous resources and ultimately lasting more than eight years. Cases involving the use of a biological agent as a weapon are particularly challenging, given the complex biology of the weapon itself, the nascent state of microbial forensics and, in this case, the potential breadth and scope of the attack. Microbial forensics grew out of the multidisciplinary areas of genomics, microbiology, and forensics, among others. It involves the development and application of methods to detect and characterize microbial samples containing a biological agent or its components, for the purpose of establishing attribution. In 2001, capabilities and understanding in microbial genomics were much less well developed than they are today. In particular, there were no complete genome sequences of B. anthracis available in 2001. These deficiencies had to be addressed at the start of the investigation. As a result, selected experts in the outside scientific community were recruited to assist in the investigation. The development and application of microbial forensics became an essential part of the scientific investigation in the hands of FBI investigators, who combined it with physicochemical analyses to narrow their search for the source of the anthrax used in the attacks.

By the time that the case was closed, the FBI had expended over 600,000 investigator work hours, involving in excess of 10,000 witness interviews conducted on six continents, the execution of 80 searches and the recovery of over 6,000 items of potential evidence. The case involved the issuance of over 5,750 federal grand jury subpoenas and the collection of 5,730 environmental samples from 60 site locations.

In September of 2008, the FBI asked the National Research Council to convene a committee to conduct an independent review of the scientific approaches used during the anthrax letters investigation, and the conclusions drawn from them. We were not asked to assess the probative value of the scientific evidence, nor to offer any view on the guilt or innocence of any person. Our committee was constituted with experts in the fields of microbiology, medicine, physical chemistry, statistics, biochemistry, public health, environmental studies, forensic science and jurisprudence. In the course of our 19-month study, the FBI provided us with approximately 9,600 pages of materials. With the report’s release, these materials are now available to the public.. With the release of our report today, all of these materials are now available to the public.

Q: Any thoughts on how a law-enforcement investigation of this nature should be conducted in the future?

Relman: In the future, among many other requirements, it will be important to ensure more timely results, more efficient environmental analysis, access to globally representative strain collections and a robust capability for characterizing less well-studied or less easily cultivated biological agents.

Officials may also need to manage expectations among the general public, policymakers and the scientific community about the conclusions that can realistically be expected from the use of microbial forensics. Because of the complexities and as yet unraveled features of microbial evolution and population structure, we may continue to be limited in our ability to trace a microbial attack agent back to its source. Of note, the federal government, through the leadership of the Executive Office of the President, has recently articulated a national research and development strategy for microbial forensics.

Future biological attacks may pose greater challenges than did this attack. For example, the biological agent may belong to a species with a more complex and less well understood population structure, it may be genetically modified in a manner that obscures its origin, or a direct sample of the attack material may not be available. This last possibility means that environmental and clinical samples, with their additional challenges, may have greater importance in a future investigation.

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