Biological Engineering, Risk, and Uncertainty by David A. Relman
M
ost discussions about the risks associated with synthetic biology—indeed, with genetic engineering in general—tend to begin and end with the same message. That is, in these revolutionary times, when the capabilities for designing and reengineering biological agents are advancing at previously unimaginable rates but have still not realized their full potential, when risks therefore remain uncertain, and where the actors are generally well-meaning people who seek important benefits for society and environment, the most reasonable approach is to exercise “prudent vigilance,” to minimize proscriptive oversight, and to avoid judgments about and limitations on research until some elusive date when greater clarity might be achieved.1 This approach may be useful in allowing scientific research to move forward, but it strikes me as a political expedient that minimizes conflict between would-be opposing factions with different values and backgrounds and as an excuse to avoid some difficult problems. Uncertainties about key features of the landscape seem to justify a reluctance to formulate judgments and promote action. I believe there are reasonable kinds of conclusions that can be made right now about when and how to conduct and publish potentially dangerous research in the life sciences. These conclusions are enabled by a more rigorous examination of the nature of uncertainty in the conduct of experiments in synthetic biology and genetic engineering. In their report, Kaebnick, Gusmano, and Murray provide a thoughtful review of numerous important but thorny issues surrounding the potential risks associated with synthetic biology.2 Among these issues are questions about the intrinsic value of scientific knowledge, tradeDavid A. Relman, “Biological Engineering, Risk, and Uncertainty,” Synthetic Future: Can We Create What We Want Out of Synthetic Biology?, special report, Hastings Center Report 44, no. 6 (2014): S36-S37. DOI: 10.1002/hast.397
S36
offs between risks and benefits, approaches for assessing the magnitudes and net balance of these competing factors, the role of societal values in these approaches, and how to operationalize the principles of deliberative democracy. These questions become yet more difficult given uncertainty about the kinds of knowledge that might result from experiments in synthetic biology and the relative magnitudes of the resulting benefits and risks. As Kaebnick and colleagues point out, the greater the uncertainties, both qualitative and quantitative, about outcomes, the more prominent the roles played by values and by variability in risk perception become, furthering the scope and scale of the challenges. Conversely, if one were able to understand or characterize these uncertainties more effectively, these tough issues would become somewhat more tractable. So what can we say about the nature of the uncertainties in this area of science? While there is variation in how the term “synthetic biology” is used, most would agree that it refers to a form of genetic engineering that is premised on rational design, with the goal of creating biological systems for explicitly specified functions and defined purposes. Some of its practitioners view synthetic biology as a form of engineering that both seeks and exploits a predictive understanding of biology. There are various aspects of deliberateness to this work. One particularly important example is the use of experimental conditions that are designed to select for specific properties of interest from among numerous, varied genetic constructions on hand—in effect, designed to encourage organisms to evolve to gain those properties. Genetic selection is immensely powerful (as demonstrated in nature) and often yields exactly what one “requests,” such as genes or organisms that have enhanced virulence or altered tropism. Thus, by examining closely the nature of the selective conditions at hand, one gains insight into the “intent” of the experimentalist, whether it is explicitly acknowledged November-December 2014/ H A S T I N G S CE NTE R RE P O RT
Much is made about the unpredictable nature of the scientific research enterprise. But the point is exaggerated—especially if considered in the context of synthetic biology. or not, and one can therefore anticipate the kinds of results that may ensue. Another example of deliberateness is the use of screening assays to identify specific genetic constructions with the properties of interest. And there are other types of deliberateness that can be “read” from the design of proposed experiments. While I do not want to suggest that one can anticipate all or even most experimental results in this or other areas of science, I would argue that much more can be understood about possible outcomes than is often assumed. Much is made about the unpredictable nature of the scientific research enterprise. But the point is exaggerated— especially if considered in the context of synthetic biology and other forms of genetic engineering. Practitioners of these disciplines are motivated by the goal of rational design, typically specify their objectives a priori, and have clear expectations about the outcome in many cases. We should also remember that research funders often issue calls for research proposals and write contracts that address requests for specified products. An example is the National Institutes of Health–sponsored Centers of Excellence in Influenza Research contract with Erasmus University that funded the deliberate construction of a highly pathogenic strain of avian influenza virus with enhanced transmissibility among mammals.3 What kinds of conclusions are enabled by these considerations of uncertainty? First, certain kinds of experiments may have predictable outcomes that demand special scrutiny before they are undertaken and may deserve to be declared unethical and morally forbidden. For example, experiments that are designed and likely to yield novel biological agents with high degrees of transmissibility and high levels of virulence or resistance to all available countermeasures may incur highly consequential risks for much of the world’s population. Typically, too, there are substantial delays before the benefits might be realized. The undertaking of experiments with high potential for significant harm to large populations and limited or much-delayed benefit threatens to violate fundamental principles of justice. The recent announcement by the U.S. government of a funding pause for certain gain-of-function studies on three pathogenic respiratory viruses, and of a more deliberative process for risk-benefit assessments, is a welcome step in focusing serious attention on these issues.4 Second, greater degrees of certainty about experimental outcomes, even if the likelihoods resist quantification,
enable more effective implementation of deliberative democracy because the scope and scale of the risks and benefits can be better anticipated, described, and understood by a more appropriately selected group of participants. Furthermore, clarity about experimental outcome facilitates the identification and selection of less risky approaches for addressing the same scientific goal.5 Third, if reducing the levels of uncertainty would produce tangible benefits for understanding and addressing important ethical concerns in this rapidly evolving area of science, then achieving those reductions should be a high priority, and technical approaches toward this end should be promoted. For example, experimental conditions that minimize selective pressures for properties of concern, as well as genetic modules that limit replication of biological agents outside of the laboratory, could be better characterized and developed through new research. I do not foresee many experiments rising to the level of risk that would justify major interventions. But the fact that we can describe and execute any such experiments today is an ironic indication of the technical prowess that we have now achieved. 1. Presidential Commission for the Study of Bioethical Issues, New Directions: The Ethics of Synthetic Biology and Emerging Technologies (Washington, D.C.: PCSBI, 2010), 124; National Science Advisory Board for Biosecurity, Addressing Biosecurity Concerns Related to Synthetic Biology (Washington, D.C.: National Science Advisory Board for Biosecurity, 2010); The InterAcademy Partnership, “IAP Statement on Realising Global Potential in Synthetic Biology: Scientific Opportunities and Good Governance,” May 7, 2014, http://www.interacademies.net/File.aspx?id=23974. 2. Gregory E. Kaebnick, Michael K. Gusmano, and Thomas H. Murray. “The Ethics of Synthetic Biology: Next Steps and Prior Questions,” Synthetic Future: Can We Create What We Want Out of Synthetic Biology?, special report, Hastings Center Report 44, no. 6 (2014): S4-S26. 3. S. Herfst et al., “Airborne Transmission of Influenza A/H5N1 Virus between Ferrets,” Science 336 (2012): 1534-41; M. Linster et al., “Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus,” Cell 157, no. 2 (2014): 329-39. 4. Office of Science and Technology Policy, Executive Office of the President, “Doing Diligence to Assess the Risks and Benefits of Life Sciences Gain-of-Function Research,” October 17, 2014, http://m. whitehouse.gov/blog/2014/10/17/doing-diligence-assess-risks-andbenefits-life-sciences-gain-function-research#. 5. M. Lipsitch and A. P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens,” PLoS Medicine 11, no. 5 (2014): e1001646.
SPECIAL REP ORT: S ynt h et ic Fu t u r e: C a n We C re a te W h a t We Wa n t O u t of S y n th e ti c B i ol og y ?
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Copyright of Hastings Center Report is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
M
ost discussions about the risks associated with synthetic biology—indeed, with genetic engineering in general—tend to begin and end with the same message. That is, in these revolutionary times, when the capabilities for designing and reengineering biological agents are advancing at previously unimaginable rates but have still not realized their full potential, when risks therefore remain uncertain, and where the actors are generally well-meaning people who seek important benefits for society and environment, the most reasonable approach is to exercise “prudent vigilance,” to minimize proscriptive oversight, and to avoid judgments about and limitations on research until some elusive date when greater clarity might be achieved.1 This approach may be useful in allowing scientific research to move forward, but it strikes me as a political expedient that minimizes conflict between would-be opposing factions with different values and backgrounds and as an excuse to avoid some difficult problems. Uncertainties about key features of the landscape seem to justify a reluctance to formulate judgments and promote action. I believe there are reasonable kinds of conclusions that can be made right now about when and how to conduct and publish potentially dangerous research in the life sciences. These conclusions are enabled by a more rigorous examination of the nature of uncertainty in the conduct of experiments in synthetic biology and genetic engineering. In their report, Kaebnick, Gusmano, and Murray provide a thoughtful review of numerous important but thorny issues surrounding the potential risks associated with synthetic biology.2 Among these issues are questions about the intrinsic value of scientific knowledge, tradeDavid A. Relman, “Biological Engineering, Risk, and Uncertainty,” Synthetic Future: Can We Create What We Want Out of Synthetic Biology?, special report, Hastings Center Report 44, no. 6 (2014): S36-S37. DOI: 10.1002/hast.397
S36
offs between risks and benefits, approaches for assessing the magnitudes and net balance of these competing factors, the role of societal values in these approaches, and how to operationalize the principles of deliberative democracy. These questions become yet more difficult given uncertainty about the kinds of knowledge that might result from experiments in synthetic biology and the relative magnitudes of the resulting benefits and risks. As Kaebnick and colleagues point out, the greater the uncertainties, both qualitative and quantitative, about outcomes, the more prominent the roles played by values and by variability in risk perception become, furthering the scope and scale of the challenges. Conversely, if one were able to understand or characterize these uncertainties more effectively, these tough issues would become somewhat more tractable. So what can we say about the nature of the uncertainties in this area of science? While there is variation in how the term “synthetic biology” is used, most would agree that it refers to a form of genetic engineering that is premised on rational design, with the goal of creating biological systems for explicitly specified functions and defined purposes. Some of its practitioners view synthetic biology as a form of engineering that both seeks and exploits a predictive understanding of biology. There are various aspects of deliberateness to this work. One particularly important example is the use of experimental conditions that are designed to select for specific properties of interest from among numerous, varied genetic constructions on hand—in effect, designed to encourage organisms to evolve to gain those properties. Genetic selection is immensely powerful (as demonstrated in nature) and often yields exactly what one “requests,” such as genes or organisms that have enhanced virulence or altered tropism. Thus, by examining closely the nature of the selective conditions at hand, one gains insight into the “intent” of the experimentalist, whether it is explicitly acknowledged November-December 2014/ H A S T I N G S CE NTE R RE P O RT
Much is made about the unpredictable nature of the scientific research enterprise. But the point is exaggerated—especially if considered in the context of synthetic biology. or not, and one can therefore anticipate the kinds of results that may ensue. Another example of deliberateness is the use of screening assays to identify specific genetic constructions with the properties of interest. And there are other types of deliberateness that can be “read” from the design of proposed experiments. While I do not want to suggest that one can anticipate all or even most experimental results in this or other areas of science, I would argue that much more can be understood about possible outcomes than is often assumed. Much is made about the unpredictable nature of the scientific research enterprise. But the point is exaggerated— especially if considered in the context of synthetic biology and other forms of genetic engineering. Practitioners of these disciplines are motivated by the goal of rational design, typically specify their objectives a priori, and have clear expectations about the outcome in many cases. We should also remember that research funders often issue calls for research proposals and write contracts that address requests for specified products. An example is the National Institutes of Health–sponsored Centers of Excellence in Influenza Research contract with Erasmus University that funded the deliberate construction of a highly pathogenic strain of avian influenza virus with enhanced transmissibility among mammals.3 What kinds of conclusions are enabled by these considerations of uncertainty? First, certain kinds of experiments may have predictable outcomes that demand special scrutiny before they are undertaken and may deserve to be declared unethical and morally forbidden. For example, experiments that are designed and likely to yield novel biological agents with high degrees of transmissibility and high levels of virulence or resistance to all available countermeasures may incur highly consequential risks for much of the world’s population. Typically, too, there are substantial delays before the benefits might be realized. The undertaking of experiments with high potential for significant harm to large populations and limited or much-delayed benefit threatens to violate fundamental principles of justice. The recent announcement by the U.S. government of a funding pause for certain gain-of-function studies on three pathogenic respiratory viruses, and of a more deliberative process for risk-benefit assessments, is a welcome step in focusing serious attention on these issues.4 Second, greater degrees of certainty about experimental outcomes, even if the likelihoods resist quantification,
enable more effective implementation of deliberative democracy because the scope and scale of the risks and benefits can be better anticipated, described, and understood by a more appropriately selected group of participants. Furthermore, clarity about experimental outcome facilitates the identification and selection of less risky approaches for addressing the same scientific goal.5 Third, if reducing the levels of uncertainty would produce tangible benefits for understanding and addressing important ethical concerns in this rapidly evolving area of science, then achieving those reductions should be a high priority, and technical approaches toward this end should be promoted. For example, experimental conditions that minimize selective pressures for properties of concern, as well as genetic modules that limit replication of biological agents outside of the laboratory, could be better characterized and developed through new research. I do not foresee many experiments rising to the level of risk that would justify major interventions. But the fact that we can describe and execute any such experiments today is an ironic indication of the technical prowess that we have now achieved. 1. Presidential Commission for the Study of Bioethical Issues, New Directions: The Ethics of Synthetic Biology and Emerging Technologies (Washington, D.C.: PCSBI, 2010), 124; National Science Advisory Board for Biosecurity, Addressing Biosecurity Concerns Related to Synthetic Biology (Washington, D.C.: National Science Advisory Board for Biosecurity, 2010); The InterAcademy Partnership, “IAP Statement on Realising Global Potential in Synthetic Biology: Scientific Opportunities and Good Governance,” May 7, 2014, http://www.interacademies.net/File.aspx?id=23974. 2. Gregory E. Kaebnick, Michael K. Gusmano, and Thomas H. Murray. “The Ethics of Synthetic Biology: Next Steps and Prior Questions,” Synthetic Future: Can We Create What We Want Out of Synthetic Biology?, special report, Hastings Center Report 44, no. 6 (2014): S4-S26. 3. S. Herfst et al., “Airborne Transmission of Influenza A/H5N1 Virus between Ferrets,” Science 336 (2012): 1534-41; M. Linster et al., “Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus,” Cell 157, no. 2 (2014): 329-39. 4. Office of Science and Technology Policy, Executive Office of the President, “Doing Diligence to Assess the Risks and Benefits of Life Sciences Gain-of-Function Research,” October 17, 2014, http://m. whitehouse.gov/blog/2014/10/17/doing-diligence-assess-risks-andbenefits-life-sciences-gain-function-research#. 5. M. Lipsitch and A. P. Galvani, “Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens,” PLoS Medicine 11, no. 5 (2014): e1001646.
SPECIAL REP ORT: S ynt h et ic Fu t u r e: C a n We C re a te W h a t We Wa n t O u t of S y n th e ti c B i ol og y ?
S37
Copyright of Hastings Center Report is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
