The Ethics of Seeking the Killer Flu
By S. Van McCrary, Health Law & Policy Institute
It occurred to me this week that October is approaching rapidly, and with it comes time for my annual flu immunization. In recent years, interest in, and research on, influenza has been expanding dramatically. A visible example of this phenomenon was the widespread media coverage of the scientific hunt for the "bird flu"--a previously unknown strain which killed a small number of persons in Hong Kong in 1997. Another manifestation of expanding interest is the ongoing search for the virus that caused the influenza pandemic of 1918, which killed an estimated 20 to 40 million persons worldwide--more deaths than occurred during the "black plague" of the 14th century.
One primary medical basis of this increased interest and research is that the influenza virus has not experienced a "shift" to an entirely new family of viruses in a substantial period of time, and such a change seems likely in the near future. Virtually all influenza virus now circulating is a variant either of the Hong Kong flu of 1968 or the Russian flu of 1977. Any transition from these two known viruses has potential to create pandemic conditions because the mutated virus will be completely unlike any one before. Currently, the flu virus mutates by what scientists call "drifting"--undergoing minor mutations in the viral proteins to stay ahead of the human immune system. With only minor changes in the viral makeup, some exposed persons will be partially immune and may only experience mild symptoms. In contrast, a "shift" occurs when the virus changes to an entirely new family, i.e., a completely new combination of proteins. No one will have immunity to such a virus and symptoms are likely to be more severe and widespread.
The latest example of the "flu hunt" occurred during August in the tiny town of Longyearbyen, Norway, far above the Arctic circle. In this remote location, scientists opened a mass grave containing the bodies of seven men who died of the 1918 virus. The researchers hoped that the bodies would be preserved in ice because the permafrost line is so close to the surface of the ground at this location. If the bodies were preserved, the researchers planned to take tissue samples from the lungs and other organs by needle biopsy. It is possible, but unlikely, that samples of live virus might be obtained in this way. Even if no live virus was obtained, viral fragments might still provide some scientific clues. The goal of the project is to determine the composition, genetic structure, and nature of the 1918 virus. Such information could lead to development of a new vaccine against this particularly virulent form of influenza, as well as new anti-viral drugs for treatment.
A major ethical issue raised by this project is safety of the research and protecting the public health. If live virus was found in the bodies and the researchers and workers were exposed, a recurrence of the 1918 outbreak might ensue. Although such an event appears unlikely, the severity of the 1918 disease demands drastic safety measures to ensure that viral particles are not released into the environment. One way to evaluate the flu research on ethical and policy grounds is to compare it with the standards developed to deal with potential biological hazards from research with recombinant DNA molecules. These standards were first established systematically in 1975 at the "Asilomar conference" on biohazards from recombinant genetic materials, and are currently codified as formal guidelines of the National Institutes of Health (NIH) at 59 Federal Register 34496-01 (1994). In addition to the guidelines, the NIH has established the Recombinant DNA Advisory Committee--a 17-member group composed of molecular biologists, physicians, ethicists, lawyers, and policy experts who regularly review proposed new research for safety and adherence to ethical and legal standards. Although the Asilomar standards are more than 20 years old and have evolved significantly as technology has progressed, the basic ethical principles on which the standards were based have not changed [Berg P, Baltimore D, et al. Summary Statement of the Asilomar Conference on Recombinant DNA Molecules. Proceedings of the National Academy of Sciences, June, 1975; 72 (6): 1981-4]. Thus, comparison with the Asilomar guidelines may prove instructive.
An overriding concern of the guidelines is that the risks presented to researchers and the public at large be minimized. Closely aligned with risk assessment is the recognition of uncertainty, i.e., that some risks are difficult to quantify given the current state of scientific knowledge. To make their specific recommendations, the Asilomar researchers sought to balance the level and certainty of potential risks with the level of containment practices and development of containment technology. The main principles are that (1) containment must be an essential part of the experimental design, and (2) the effectiveness of containment should match as closely as possible the estimated risks (in the event risks are not determinable, error should fall on the side of caution). In addition, the guidelines require that: (1) voluntary consent be obtained from field and laboratory workers after appropriate disclosure of the nature of the experiment and the possible risks; (2) high quality training of personnel be an essential component of good containment practices; and (3) ongoing surveillance of workers' health be maintained to ascertain whether safety is being preserved. Generally, the ethical approach of the guidelines is utilitarian in origin, recognizing the moral acceptability of a tradeoff between risk to the researchers and the public, and possible benefits to society as a whole.
The guidelines specifically categorized containment practices into four groups, as follows: (1) minimal risk--where the hazards accurately can be assessed and are expected to be minimal (requires only lab coats, mechanical pipetting devices, and other routine precautions); (2) low risk--involving novel biotypes where existing knowledge indicates there is limited potential for harm (requires limited lab access, biosafety cabinets for storage of samples, etc.); (3) moderate risk--where there is a probability of dealing with a biological agent with significant pathogenicity (requires gloves, laminar air flow hoods, filters for all waste product lines, etc.); and (4) high risk--where the potential for ecological disruption or pathogenicity of the organism could be severe and thereby pose a serious biohazard to lab personnel or the public (requires air locks, a negative pressure environment, clothing changes and showers, waste treatment systems, etc.).
Major issues for applicability of the Asilomar standards to the influenza research include: (1) whether the containment technology to be used is properly matched to the risks of contamination as currently understood; (2) whether all laboratory and field workers involved received appropriate training and disclosure of potential risks, and voluntarily consented to participate; and (3) whether generalizable knowledge is likely to result from the project.
Fortunately, the researchers involved in the Norwegian "flu hunt" proved to be very concerned about the ethical implications of their work. A member of the team stated that the "first obligation" of the researchers was safety--to protect against the possible escape of viral particles into the environment. To achieve this goal, strong containment precautions were taken against spread of infectious organisms, including: (1) covering the entire site with a negative-pressure tent containing a special air lock; (2) using "space suits" with self-contained breathing apparatus; and (3) transporting all samples to secure laboratories prior to working on them. The potential hazard posed by the 1918 influenza virus clearly meets the criteria established in the "high risk" containment category and requires the most stringent containment precautions applicable; even if the actual risk is later determined not to be severe, there is sufficient uncertainty regarding the lingering virulence of the organism to warrant this degree of caution. Containment technology today has progressed to the point where safeguards are adequate to lower the risk to the point where it is counterbalanced by the expected social benefits. Further, the potential for acquiring generalizable knowledge appears high from this research and the goal is persuasive--to prevent another influenza pandemic of the type experienced during 1918. Thus, even though there is a small but real risk from this research, the potential benefits appear clearly to outweigh such a risk from a societal perspective. If the researchers are successful in determining the complete genetic structure of the 1918 virus, the benefits in terms of preventing future devastating outbreaks could be incalculable.
As a postscript, the preliminary results of the project were made public in early September. It turned out that the bodies were not in permafrost and thus had undergone some decomposition; however, the researchers were able to obtain tissue samples from some of the bodies. This makes it likely that there might be less valuable information derived from the samples than if they had consistently been frozen. Nonetheless, the team expressed optimism and reported that they could know within three months whether the samples were likely to produce significant results. It may be up to three additional years, before the analysis is completed.