The ethics of synthetic biology: next steps and prior questions.

The Ethics of Synthetic Biology: Next Steps and Prior Questions by Gregory E. Kaebnick, Michael K. Gusmano, and Thomas H. Murray

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majority opinion seems to have emerged in scholarly analysis of the assortment of technologies that have been given the label “synthetic biology.” According to this view, society should allow the technology to proceed and even provide it some financial support, while monitoring its progress and attempting to ensure that the development leads to good outcomes.1 The near-consensus is captured by the U.S. Presidential Commission for the Study of Bioethical Issues (PCSBI) in its report New Directions: The Ethics of Synthetic Biology and Emerging Technologies, which arguably marked the end of a preliminary round of analysis about the ethical and policy questions raised by synthetic biology. Like a number of other, earlier documents issued by various groups around the world, the report called attention to questions about how the technology will be used; whether it might be misused; what sorts of accidents might happen along the way; the economic, environmental, and social impacts of the eventual applications; whether the very idea of “synthetic biology” should be troubling; and how the debate over all of these questions will be conducted. Also like most similar documents, however, while it called for careful monitoring and oversight of technology, it did not recommend any significant new constraints on its development and use. The commission’s stance 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. DOI: 10.1002/hast.392

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was that it would be “imprudent either to declare a moratorium on synthetic biology until all risks can be determined and mitigated, or to simply ‘let science rip,’ regardless of the likely risks.”2 The questions that should be asked of synthetic biology have not been put to rest, of course, and cannot be put entirely to rest. Partly this is just because of factual uncertainties; the technology is still emerging, and the possible outcomes are still uncertain. Partly, too, it is because of conceptual uncertainties: how to articulate and how to address the questions also remain up for debate. In this report, we will take stock of the current consensus, comment on some of the major points of disagreement, and identify the next steps for the debate. In part I, we offer a brief overview of the research and applications commonly grouped together under the heading of synthetic biology, partly in order to set the stage for the rest of the discussion and partly because we want to highlight some conceptual problems that attend the very label given this field. In parts II, III, and IV, we take up, respectively, three broad classes of concerns that arise in the context of synthetic biology: concerns about the intrinsic or inherent value of doing synthetic biology, concerns about the concrete harms and benefits of doing synthetic biology, and concerns about justice. Addressing these concerns requires a method for bringing the public’s values to bear on policy-making concerning emerging biotechnologies; in part V, we discuss the challenges in developing such a method.

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I. Synthetic Biology

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he emergence of a sizable body of commentary on synthetic biology notwithstanding, what synthetic biology is, and indeed whether it is distinct from some other, older biotechnologies, is contested and still remains unclear.3 The core idea in the term “synthetic biology” is not merely to alter biological systems but to develop and employ strategies for doing so that make possible the rational design and synthesis of biological systems that serve human ends.4 Under this broad understanding, synthetic biology might encompass the fairly limited alteration of plants and animals that once would have been labeled simply “gene transfer” or “genetic modification.” Nonetheless, the work typically considered paradigmatic of synthetic biology consists of significantly reworking an organism’s metabolism both by eliminating genes that control for unwanted metabolic pathways and by inserting genes, or sometimes suites of genes drawn from several different kinds of organisms, to create new metabolic pathways. In principle, such ambitious reengineering could be applied to complex organisms,5 but to date, it is mostly limited to single-cell constructs. At least three general lines of work are prominent in synthetic biology.6 For many people, probably, the first inkling of the field’s existence was the announcement by the J. Craig Venter Institute in May 2010 that it had created the world’s first “synthetic organism”—which resulted from inserting a synthesized version of a Mycoplasma mycoides into a cell body of Mycoplasma capricolum, which then turned into a fully functional cell with the attributes of M. mycoides.7 The goal of this line of work, which JCVI calls “synthetic genomics,” is to develop simplified microorganisms that can be used as starting points for other alterations. A second line, sometimes called “biobricks” or “bioparts” development, consists in trying to develop simplified, standardized genetic sequences that predictably cause a microorganism in which they are placed to perform very specific tasks and can be combined with each other to create organisms that perform more complicated tasks. This line is exemplified by the work associated with the Biobricks Foundation and the annual International Genetically Engineered Machines competition.8 Besides these two broad, somewhat complementary lines—the synthesis of simplified genomes and the synthesis of biobricks to insert in genomes—is an assortment of other lines that for the time being, until one of them rises to special prominence and deserves independent treatment, might be grouped together under the broad heading of “novel biochemistries.” This kind of work is represented by research aimed at creating “protocells” whose mechanisms

for maintaining internal organization, metabolism, and replication (if needed) might be created from scratch, according to new designs, and with new materials—perhaps leading to organisms that did not use DNA to record information about cell structure and function or even to organisms whose basic structures were not carbon-based.9 Other novel biochemistries within synthetic biology include genetic creations that are entirely unknown in nature, such as causing DNA molecules to spiral in the reverse direction (a prospect referred to as “mirror life”).10 Synthetic biology is widely thought, by both proponents and critics, to have the potential to lead to very significant industrial, medical, agricultural, and environmental applications. It is frequently described as a socially transformative technology that will usher in what amounts to a new industrial revolution, in which modified microorganisms become the new means of production.11 Some of the leading spokespersons for synthetic biology also believe that it will help bring about a democratization of the means of production, as people with relatively modest biological training will be able to assemble biobricks to create innovative and useful biological constructs.12 Some of the potential applications so far developed would rely on biobricks. In the 2006 IGEM competition, for example, a team of college students from Edinburgh University developed a design for a system that could be inserted into Escherichia coli to create a mechanism for testing well water for arsenic contamination, a common problem in the developing world.13 The biobrick approach faces considerable hurdles, however, as a reliable strategy for developing applications.14 The most promising large-scale applications, in fact, do not clearly reflect any of the lines of research described above. They consist of identifying an existing organism with desirable properties and genetically modifying it to build on or accentuate those properties. There is no clear line between this kind of work and earlier work.15 Some critics refer to synthetic biology simply as “extreme genetic engineering.”16 The lack of a distinction is especially well exemplified by an endeavor known as the glowing plant project, which involves the insertion of some genetic sequences from a firefly into a mustard plant, causing the plant to glow faintly;17 the alteration has been widely billed as synthetic biology, but it has been possible for some decades, although at one time it would have been called gene splicing or genetic engineering. In short, whether the label “synthetic biology” refers to anything new and distinctive turns out to be highly questionable. This has an important implication for the conceptual uncertainties around synthetic biology: The term

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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suggests that a new field has emerged, which suggests in turn that a new or special set of ethical considerations may have arisen. In particular, insofar as the word “synthetic” suggests a degree or kind of mastery, it is more aspirational than accurately descriptive of the current state of affairs. JCVI’s announcement that it had created a “synthetic organism” reflects this problem. That term vaguely suggests the creation of a novel entity, but in fact, the organism was a copy of an existing organism. Strictly speaking, too, only the genome was synthesized; the overall organism was created by combining the genome with a naturally occurring cell that had been emptied of its own genetic material. JCVI argued that the entire organism was synthetic because the synthetic genome took over the cell body and remade it,18 but the accuracy of that claim depends on a certain set of metaphors about genes, according to which genes are not merely key elements of cells but masters of them. Finally, even the bare fact of synthesizing a genome is not quite new, if “synthetic” means merely that humans were centrally involved in the construction. What was unprecedented here was that the JCVI scientists took a relatively long route to accomplish the synthesis—writing out the organism’s genome letter by letter. In this case, “synthetic organism” suggested a greater accomplishment and a greater degree of human control than had really been achieved, and it promoted a particular understanding of genes that may in fact not be the most useful. In this article, we use the term “synthetic biology” to refer to the use of genetic technologies to modify or create

microorganisms to serve human purposes, and we focus on nearer-term possibilities rather than on more distant possibilities. We do not, for example, discuss the possible reengineering of the human genome or the development of plants designed to grow from seeds into houses, nor do we address applications involving novel nucleic acids or “mirror” DNA. We will try to bear in mind that there is no clear demarcation between what counts as synthetic biology and what counts as genetic engineering and that the notion of “synthesis” may subtly redirect our attention. The complexity of synthetic biology is reflected by the array of cases that figure in this report. One of these case studies is defined by its goal: developing organisms that are designed for producing fuel. Two others are defined by the context in which the synthetic organism would be found; these are the development of organisms for deliberate release into the environment and the development of organisms for insertion into the human microbiome (that is, the assortment of microorganisms found on and in the human body, especially the digestive system). A fourth is defined by the social context in which work on it occurs; this case is the development of organisms in small, privately owned labs that are not associated with any major research university—so-called DIYbio or garage bio. For the sake of brevity, we will refer to these simply as the biofuel case, the environmental release case, the microbiome case, and the DIYbio case.

II. Humans and Nature: The Prospect of Synthesizing Living Things

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he threshold question for synthetic biology is whether the very prospect of synthesizing organisms is intrinsically or inherently problematic, whether or not it turns out to be good or bad for people. Humans already alter the natural world in dramatic ways; ought that capacity be extended to living organisms in the way that synthetic biology allows, such that we could end up with what might plausibly be called artificial living things?19 This threshold question is sometimes loosely referred to as the “moral” objection to synthetic biology, although, in point of fact, moral values permeate all aspects of the assessment of synthetic biology. Claims about the proper human relationship to nature are difficult to articulate and examine. As traditionally understood in the Western analytic philosophical canon, anyway, morality is about relations between sentient creatures, and moral obligations are generated only by one or another aspect of sentience—happiness, for example, or the capacity of self-determination. A complete examination of concerns about the very idea of synthesizing micro-

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organisms would require venturing into this philosophical terrain.20 Here we merely note that many people want a brake pedal as well as an accelerator on human intervention into the natural world. They believe that we should try to strike a balance between altering the natural world to accommodate human behavior and altering our own behavior to accommodate the natural world.21 Perhaps this view is firmest and clearest in disputes about preserving wildernesses and wildlife. Many people say, for example, that we should try to avoid the human-caused extinction of species and limit human-caused destruction of those places in the world that, so far, still show comparatively little human alteration—even though we may in other places seek to advance human industry. The idea of balance is key here, although it suggests that judgments about precisely what interventions to permit, which to limit, how to go about limiting them, and when (sometimes) to promote them, will be complicated and often uncertain. Few would argue that the concern about altering nature is a moral trump, always winning out over November-December 2014/ H A S T I N G S CE NTE R RE P O RT

Insofar as the word “synthetic” suggests a degree or kind of mastery, it is more aspirational than accurately descriptive of the current state of affairs. other kinds of moral concerns. However, the many cases in which that concern loses out to other concerns do not show that preservationism is hollow, either. (In short, the concern about nature is not completely undermined by giving counterexamples; it’s only complicated.). We often strive precisely to alter nature—indeed, we do that not only because we want to make the world a better place in which to live but because we also value human ingenuity and mastery in and of themselves—but as human ingenuity has grown in power, we have also begun to ask whether we may not sometimes be going too far. Contrasting Considerations for the Human Relationship to Nature

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or those who aspire to balancing alteration of nature with accommodation of nature, synthetic biology presents an interesting case. On the one hand, synthetic biology can be seen as inherently throwing down the gauntlet. The most general definition of synthetic biology—that is, the application of engineering to biology with the goal of turning organisms into machines for human purposes and maybe even of creating life—sounds like the clearest case imaginable of adjusting nature to accommodate human ends.22 Also, the growing social prominence of synthetic biology might have the effect of promoting a discourse of adjusting nature over a discourse of adjusting to nature.23 Perhaps it would even encourage us to think that our power to adjust nature means we don’t have to adjust to nature. There will always be a technological fix to the environmental problems caused by technology. (For example, we could combine synthetic biology with reproductive technologies to achieve the “de-extinction” of species that we have driven into extinction.24) On the other hand, there are reasons to think that biological engineering does not necessarily change the human relationship to nature, and that what matters is simply the environmental impact. To begin with, the general definition of synthetic biology is arguably not a good basis for a moral assessment of synthetic biology. One problem with it is that it may be misleading; biological systems may not ever submit to engineering and organisms may not ever be like machines—except in the trivial sense that they can be modified to do things that are useful for humans. (In that

sense, biological machines are already all around.) Another problem with the general definition is that it forces us to think in abstract, purely conceptual terms—to ask whether the idea of synthetic biology will lead to a new understanding of nature, life, or humanity. Yet the very idea of aiming for a balance in our relationship to nature encourages us to think concretely, rather than in abstractions: the goal is to think about which activities to condone, constrain, or ban and which to permit. It may be more helpful, then, to consider specific applications, lines of research, or ways of conducting research and not to be overly concerned with a general definition of synthetic biology. When we do that, when we think more concretely about synthetic biology, the effect of the field on the human relationship to nature arguably looks less significant. Partly this is because of the kinds of organisms involved. To date, the most promising applications of synthetic biology are probably better described as involving the modification of existing kinds of organisms rather than the development of new ones. Also, the applications to date are mostly about microbes. The concern about human control over living things is arguably best understood not as a general concern about the human relationship to all living things (let alone to Life with a capital “L,” understanding that as invoking a special ontological category). Instead, perhaps, it varies as we consider different categories of living and near-living things (the category of life may not even be sharply delineated). There are prions, viruses, prokaryotes, single-celled eukaryotes, plants, fungi, and animals with varying kinds of biological and moral complexity, from nematodes to humans.25 When we consider this array of entities, however, it may become hard to resist the thought that, just as intervening to end the life of a living thing may have a different moral valence depending on the kind of thing it is, so we may draw moral distinctions about intervening in the way it goes about its life or how it comes to be alive or the properties it has while it lives. Synthetic biology’s rather modest effect on the human relationship to nature, at least when we look at it concretely, is also partly a function of the kinds of applications at stake. Most synthetic biology applications envisioned so far would be located in industrial or medical contexts—contexts in which human alteration of nature is already a given—and amount to replacing one form of alteration with


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another. One way of considering whether producing fuel by “synthetic organisms” changes the human relationship to nature is to try to explain just how it is fundamentally different, in terms of the extent of human intervention into the natural world, from extracting, processing, and transporting oil. Synthetic biology may not be intrinsically attractive to someone who has a preservationist mindset, but is making fuel with synthetic organisms really worse than how it’s done now? There are two ways of thinking about that question. One has to do with whether making fuel with humanmodified microbes is inherently more at odds with a nature-accommodating discourse than is making fuel by extracting and processing raw materials. Another is about the effect on particular parts of the natural world that a nature-accommodating person would likely want to conserve—naturally occurring species, places, ecosystems, and so on. In environmentalism—arguably the paradigmatic case for moral concern about the human relationship to nature—the concern focuses on the replacement of natural phenomena with artifactual phenomena, especially when the replacement amounts to the destruction of nature, but synthetic biology applications need not replace nature and are not necessarily destructive. The creations of synthetic biology might end up simply standing alongside the realm of nature as we know it, and might, just possibly, offer nature-benefiting, even nature-preserving, opportunities. Whether synthetic biology turns out to be nature-destructive will depend on what applications are developed and how they are executed. (Of course, there is little reason to believe that synthetic biology will be a magical techno-fix, solving everything; if we are concerned about the preservation of nature, mostly we must limit our use of natural resources and constrain our production of waste.) How the applications affect the natural world will often be very complicated, of course. Conventional biofuel production offers some helpful lessons on this score. Two of the cases we considered—the development of organisms for deliberate transfer to the environment and the application of synthetic biology to the human microbiome—are especially complicated. These applications are intended specifically to alter natural environments, and the organisms would be designed to survive in natural environments. Compared to applications in which synthetic organisms could be contained in sealed systems (as much to protect the organisms from the environment as to protect the environment from the organisms), predicting their effects could be very difficult. These applications warrant particularly careful evaluation. However ambitious the applications of synthetic biology become, they will arguably never amount to “creating Life” or “playing God.” Protocells and “mirror life” would be the best candidates for the label “new forms of life” and S8

would therefore provide the best reason to think that humans have engaged in “creation,” but what even that could prove about human powers is limited.26 If Life is a category above and beyond the material world, and if the material world marks the limits of human agency (even for scientists!), then nothing that occurs in a laboratory is plausibly understood as creating It. Similarly, if divine powers are by definition powers that categorically exceed those of humans, then scientists can play God only in the way a child can play at being an adult; they cannot actually become Gods. There might be a deeply unattractive hubris involved, but not a new world order. Scientists cannot recreate Creation. Private Concerns and Public Engagement

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he upshot of such considerations seems to us to be this: Synthetic biology is the highly skilled alteration of nature, yet it might not significantly change our understanding of the human relationship to nature. The near-term, more plausible applications, at least, do not necessarily lead either to significant conceptual shifts in our understanding of the human relationship to nature or to tangible changes in nature. Some applications and some lines of research that are in very early stages of development might have more dramatic effects, but they should be assessed on their own merits. What are the next steps in thinking about how synthetic biology might change the human relationship to nature? Neither this nor any other analysis will decide once and for all whether synthetic biology is intrinsically problematic. Given a variety of conflicting and evolving ways of understanding the key terms and no way to show that any single understanding is correct, there can be no one final right answer about what is “natural,” nor about the value of nature, nor about what sorts of behaviors conflict with or square with that value.27 Worse, the analysis cannot simply be delivered by a few commentators; it has to be made at a societal level. This is just what it means to talk about how science (as a social endeavor) might or might not change “our” understanding of the human relationship to nature. It is necessary, then, somehow to more broadly engage the public in the debate. At the same time that we are engaging the public on this question, it is necessary to take a step backward and ask whether and how such concerns (however we articulate them) should be taken up in public policy and political discourse.28 There is a strong sentiment in U.S. politics and in liberal political philosophy that government ought to be wary about taking sides in moral debates that do not address issues central to the role of a democratic government. Government policy should adhere, that is, to a principle of neutrality. This sentiment calls for further examinaNovember-December 2014/ H A S T I N G S CE NTE R RE P O RT

There can be no one final right answer about what is “natural,” about the value of nature, or about what sorts of behaviors conflict with or square with that value. tion. What are the arguments for and against that view, and even if it stands up, how should it be applied? First, which debates are not central to the role of a democratic government? That is to say, are debates about how synthetic biology (and perhaps other biotechnologies) might change the human relationship to nature outside the ambit of a democratic government, and if so, then what kinds of policies about synthetic biology are excluded? Insofar as the regulation of biotechnology is based on assumptions about the “fundamental divisions between nature and culture, moral and immoral, safe and risky, God-given and human made,” as Sheila Jasanoff argues, then it cannot be handled by the narrower, thinner moral distinction of liberalism and requires “principles of governance based on older orderings and classifications.”29 Returning to those principles would expand the role of government into spheres that are considered private in liberal theory. Further, if governance in general depends on “fundamental divisions between nature and culture, moral and immoral, safe and risky, God-given and human made,” then advances in synthetic biology may also pose a fundamental regulatory challenge insofar as they might eventually simply undo those distinctions. And if synthetic biology poses such a challenge, then the state does not have to be neutral with regard to it. Of course, such “fundamental divisions” are not uniquely raised by synthetic biology, but are common to a plethora of developments in social arrangements as well as a broad range of novel technologies. For example, opponents of gay marriage argue that it is unnatural, immoral, unsafe (to children), violates a Godgiven institution, and so on. Arguments of this sort run along all the supposedly fundamental distinctions mentioned above and remind us why we ought to be cautious about using such arguments to set aside liberal neutrality. Second, what does it mean to “take sides” in those debates? Decisions that governments make with regard to the regulation of synthetic biology will tend to favor some conceptions of the good life over others. But since neutrality with regard to the consequences of government action would be very difficult and highly restrictive, the neutrality

principle is often interpreted as calling for only neutrality of “intent” or “justification,” which means that the government may not use arguments about which ways of life are most worth living as a justification for government action.30 Nevertheless, it possible that even some partiality of intent may be compatible with neutrality. Although a neutral government should not close down conceptions of the good (unless they are incompatible with the conception of the good that is necessary for liberalism), possibly it may lend some level of support to conceptions of the good, particularly if there is a strong consensus in the population.31 The hope is that a neutral state will allow citizens to “persuade others of the value of their way of life” while protecting those that fail to do so from negative state action. There is powerful evidence that moral arguments are frequently invoked to justify government action in the United States. Throughout American history, moral arguments have been central to debates about slavery, women’s suffrage, temperance, civil rights, tobacco, and drugs.32 Some of these moral arguments would be permitted in a neutral state because they are foundational to the liberal state (women’s suffrage, for example, is grounded on the basic equality of human beings, which is a core liberal moral commitment), but others (about tobacco and drug control, for instance) may be justified only because they reflect strong citizen support. If the degree or nature of government’s uptake of moral positions depends partly on the strength of citizen support for those positions, then is there some way of gauging that support other than through the democratic process itself? Since the moral values at stake are not easily articulated or understood, and if the connections between those values and synthetic biology are complex, and since concerns about the human relationship to nature are sometimes blended with more familiar consequentialist concerns, straightforward votes or surveys may be inadequate. Instead, as the PCSBI’s commission seems to have suggested, some sort of ongoing public deliberation about them seems warranted. Later in the paper we return to this suggestion and discuss its implications for policy and practice.


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III. The Effects on People: Risks and Potential Benefits

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nother set of moral concerns about synthetic biology has to do with possible effects on human welfare. Synthetic biology’s potential benefits include the development of new products and new ways of making familiar products in an extremely wide range of spheres, ranging from medicine to the petrochemical industry, the food industry, and cosmetics. Some of the most heralded applications so far have been in the first two domains, exemplified by the development of E. coli and then yeast that produce artemisinic acid (a precursor to artemisinin, which is currently the best-known treatment for malaria)33 and the development of a variety of organisms that can make fuels of different sorts and in different ways, sometimes by processing plant sugars and sometimes through photosynthesis.34 The biofuel applications have so far proven technically feasible but not economically viable; they are too inefficient to compete with conventional methods of making fuel. More promising applications, then, appear to be the production of chemically similar molecules that are used in much smaller quantities and command a higher price. Such molecules are common in fragrances, cosmetics, and flavorings, for example.35 Other possible uses of synthetic organisms are in public health (E. coli that can test for arsenic in drinking water36), agriculture (crops with new traits37), and food (yeast that makes vanilla38). A recent report sponsored by the Wildlife Conservation Society considers whether synthetic biology might even be used for species conservation, perhaps by bringing back extinct species.39 Synthetic biology can also contribute to conventional, “analytic” biology; synthesizing and modifying biological systems can contribute to our understanding of how they function. The concerns are just as varied. First on the table are health risks, starting with concerns about the safety of those working with synthetic organisms and running through broader public health concerns about the effects of organisms that escaped or were deliberately released into the environment or into human subjects (and then perhaps evolved into new forms, or exchanged genes with wild-type organisms to develop new forms, or simply turned out to have new properties once they were interacting with a new environment). A variety of safety mechanisms have been proposed that might help in avoiding or mitigating these risks. These mechanisms range from physical barriers between the organism and the environment to biological strategies that would ensure the organisms could not survive in the wild. The biocontainment strategies are clever and helpful, but given the complexity and dynamic nature of the systems in question—capable of evolving into new S10

designs and exchanging parts with other systems—they are probably not adequate by themselves. Perhaps the most serious and certainly the most arresting of the concerns are the fears that synthetic biology might provide powerful but unpredictable new tools for making biological weapons.40 These could be aimed at human targets, but conceivably great public health damage could be achieved with agricultural or environmental targets. The announcements in 2011, by two different teams of researchers, of the development of highly lethal and possibly more transmissible forms of bird flu (H5N1) gave legs to this concern; the work did not involve synthetic biology as it is understood here, but the tools of synthetic biology could be put to similar effect.41 A decade earlier, work on mousepox suggested the possibility of engineering a form of smallpox that would be more lethal than the form that was eradicated in the twentieth century and would also resist the vaccine.42 Many other, more prosaic worries have to do less with synthesized microorganisms themselves than with the forms of industry they could bring about. Synthetic organisms that proved economically viable for making high-volume materials like fuel might require a vast commitment of resources—land given over to growing sugarcane, for example, to feed E. coli that produced fuel from plant substrates, or land and water given over to ponds for producing fuel photosynthetically using modified algae. Organisms that produced low-volume but high-margin chemicals would require less input, but since those chemicals are sometimes derived from plants grown or gathered in developing countries, their output might have an outsized social and economic impact. The broad array of possible harms and benefits has been identified in many places, including the reports mentioned earlier. The key concept is that, at this stage, many of the outcomes are mere possibilities; for a variety of reasons, they might not pan out. The challenge is to work toward investigating them more closely and putting the appropriate policy in place. What makes this work difficult is that, precisely because the technology is emerging and is thought to be transformational, both the final products and the impact they might have on society are as yet unknown. It would be short-sighted, if not irresponsible, to make any final recommendations about synthetic biology; rather, we must focus on the conditions and processes for evaluating it.


There are no unique physical characteristics that organisms have just by virtue of being genetically modified. In fact, a synthetic organism could be identical to a naturally occurring one. Investigating Possible Outcomes

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handful of general practical recommendations can be made, the overarching theme of which is that a lot of watchfulness and stone-turning is needed. Commentator who have addressed the biosecurity concerns have recommended a combination of professional self-monitoring, governmental oversight, and research into technical advances that could promote security and safety.43 Peaceful applications also need study. First, a high level of transparency is needed about the research and potential applications. Second, investigating the possible benefits and harms requires a broad disciplinary array of experts. Understanding the risk an organism might pose in the environment, for example, may require the involvement of epidemiologists, ecologists, systems biologists, and public health experts as well as genetic scientists.44 Third, the investigation must be iterative, occurring over time, because what is learned as research unfolds might drive changes in the understanding of the eventual outcomes. The assessment should begin early in research and should continue after any application (after a product involving synthetic biology has been marketed, for example). Fourth, given the likelihood, perhaps even inevitability, that the technology and applications will change over time, both the investigation of outcomes and the regulatory mechanisms put in place to control them will need to be flexible. It is not possible to make a priori decisions about the acceptability of broad categories of applications. At the outset of research on biofuel applications, for example, we may well not know enough about the microorganisms and the effect of the proposed modifications to say that biofuel applications in general will have a good or bad benefit-harm trade-off. Decisions will have to be made product by product, organism by organism—a sixth recommendation. At the same time, the inability to say decisively that the work will be beneficial suggests a need for broad constraints, of the sort described above, on how the research unfolds and applications are brought online. These recommendations are roughly in line with more detailed recommendations offered by the PCSBI and the International Risk Governance Council, but they stand in contrast to the position in “The Principles for the Oversight of Synthetic Biology.”45 “The Principles” calls for a moratorium on the release and commercial use of

synthetic organisms, cells, or genomes until several conditions are met, including that a “full and inclusive” risk assessment of the technology has been conducted, that national and international oversight mechanisms specific to the special challenges of synthetic biology are in place, and that all of the alternatives to the applications have been considered. Our sense is that these conditions are not practicable and, if attempted, would not be meaningful, given the huge variety of things that “synthetic biology” refers to and the uncertainty about how the applications might actually go. They might also not be helpful, if broad policy decisions reached now did not have the flexibility to adapt as the technology and its possible applications evolve and as our understanding of it improves. Finally, at least for the time being, they are not necessary, since synthetic biology is very closely related to existing lines of biological research and most organisms created using its techniques are very unlikely to pose stark health, safety, or environmental risks. Also, synthetic organisms will usually have been designed specifically to do something that tends to make them less likely to flourish in the wild—they will be designed to produce too much of some product, or their metabolic processes will have been hijacked to serve other ends, or metabolic processes that compete with the desired processes will have been eliminated. In order to eliminate undesired traits and to facilitate the design process itself, synthetic organisms will sometimes have been genetically simplified, and the simplification will tend to deprive them of genetic resources that would allow them to respond to new challenges—that is, they may lack adaptability and resilience. The recommendations in “The Principles” may stem in part from a conflation of the intrinsic concerns about synthetic biology and concerns about what they may do in the world. The document says that synthetic biology–specific oversight mechanisms are necessary in order to “account for the unique characteristics of synthetic organisms and their products.” But there are no unique physical characteristics that organisms have just by virtue of being genetically modified. (In fact, a synthetic organism could be identical to a naturally occurring one.) The unique characteristic possessed by synthetic organisms is just that they have been synthesized, but to object to this characteristic is to express a concern about the very idea of synthesis—a concern


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about whether synthetic organisms are intrinsically troubling. This is an important and complex concern and one worth a careful hearing, but to treat it as if it is a concern about risks is to obscure it and to do it a disservice. Our sense is that the concerns about risks and potential benefits can be addressed more responsibly—and more effectively—by assessing specific applications and lines of research. With organisms that are designed to be physically contained, the risks and potential benefits will be relatively easy to understand. Some other organisms, however, warrant very careful study—particularly those designed to be robust enough to withstand exposure to the environment. Organisms intended for deliberate environmental release, including for release into the human microbiome, meet this description. “The Principles” seems right, however, to point out that synthetic biology is not a social necessity. We could address the social problems at stake with other means, and which means is best (or how multiple strategies should be combined) would ideally be guided by the public interest. Moreover, since some synthetic biology applications might have fundamentally irreversible negative consequences, it would be wise to think those applications through pretty well before launching into them. A general moratorium on synthetic biology goes too far because it treats less worrisome and more worrisome applications equivalently, all as involving organisms with “unique characteristics.” But in the absence of a general moratorium, we still should go slowly—slowly enough that a careful consideration of consequences is possible. Deliberation calls for patience. How to institute a don’t-hurry approach is beyond the scope of this report, and it will certainly be a challenge in a world that is all about getting payoff as quickly as possible, but some formal method that creates space for dialog and for taking stock seems necessary. Conceptual and Moral Questions

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n the questions about outcomes, just as on the concerns about the human relationship to nature, we must go back to some underlying questions at the same time that we are taking practical steps to consider the tradeoffs between possible benefits and harms. Two large philosophical issues need to be taken on more directly. One is about the “ethics of knowledge”—a study of “questions about the ethics of producing and disseminating certain types of knowledge, not merely the ethics of how scientific knowledge is produced.”46 Perhaps research that is aimed at producing and disseminating knowledge of, for example, how to produce more dangerous forms of H5N1 and smallpox should not be permitted. There is a very strong presumption in science to permit well-conducted research to be published. This presumption

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reflects some practical claims—that dangerous knowledge ultimately cannot be prevented from coming into the world and that, at least in biology, distinguishing between helpful and dangerous work is often impossible because results that are seemingly innocuous as presented might still be put to dangerous use in different contexts. Also, some hold that, insofar as we are trying to limit the harm that might come from a line of research, publishing the research is still ultimately helpful because it allows for other scientists to work on responding to the threats it poses. In addition, however, the presumption reflects the intrinsic value given to liberty, advancing human understanding of the world, and sharing knowledge. The 2011 debate over new and dangerous forms of bird flu showed that the thinking about these issues is at something of an impasse. The research was eventually published, but only after a public feud among the members of the National Science Advisory Board on Biosecurity about the wisdom of publishing it. Partly, the decision seems to have been forced by the lack of good alternatives to full publication.47 Addressing the ethics of knowledge may require not only the philosophical task of sorting out these different considerations (clarifying them and assessing their significance) but also the practical task of developing institutions and systems that would allow for a richer array of possible resolutions. The ethics of knowledge is difficult in part because, to some degree, it asks us to make trade-offs between quite different—perhaps incommensurable—moral considerations—liberty and human understanding versus safety. In part, however, the difficulty stems from underlying uncertainties about how actually to think about risks and potential benefits. This is the second large philosophical issue that needs to be taken on in order to make wise trade-offs concerning synthetic biology’s benefits and risks: the philosophy of risk. What’s the best way of assessing possible outcomes and using our understanding of them to guide action? The problem is that weighing potential benefits and risks is a much more complex process, not only factually but also conceptually, than it is sometimes thought to be. Conceptually, an especially complex matter is how the weighing of risks and potential benefits involves values. There is a long-running debate about the role of values in formal impact assessment mechanisms and in related debates about how those mechanisms compare to “the precautionary principle.” There are at least two dimensions to it. First, there is debate, or at least lack of clarity, about whether impact assessment should explicitly incorporate discussion of values or should instead aim for objectivity by setting discussion of values to the side. Second, if values cannot or should not be eliminated from impact assessment, disagreement remains about what the values are and what role they should play. November-December 2014/ H A S T I N G S CE NTE R RE P O RT

Concerns about risks and potential benefits can be addressed more responsibly and more effectively by assessing specific applications and lines of research. The debate about whether values should be part of impact assessment stems from the fact that the formal methods commonly employed for this task in the United States—risk assessment (RA) to estimate the probability and severity of potential harms and cost-benefit analysis (CBA) to compare economic analyses of estimated costs and benefits—ostensibly were developed precisely as a means to ensure that the assessment of outcomes is not biased by the interests of any special in-power group but would instead reflect the broader interests of the public. These methods therefore aim for analytic clarity and repeatability, achieved through the employment of quantitative models—what Deborah Stone calls the “rationality project.”48 RA provides tools for determining whether a causal relationship exists between an entity or project and hazards to human health or the environment, the strength of the relationship, the extent of exposure to the hazards, and the probability and consequence of exposure.49 CBA is a way of deciding whether to proceed with a project by estimating in monetary terms the costs and benefits of the project.50 By looking to revealed preference, understood as a matter of market choice and averaged across a community, CBA aims to model decision-making in a way that is objective. Criticisms of these tools include concerns about the plausibility of an objective, analytic method for assessing potential outcomes. A number of commentators hold that the critical steps in RA, for example—the identification of risk and the gauging of severity—depend partly on nonanalytic and emotional aspects of human judgment and are significantly shaped by culture and perspective.51 What counts as a “risk”? Is risk appropriately viewed as an aggregate measure (or is it necessarily connected to the perspectives of particular individuals)?52 To what degree should the “size” of a risk be considered instead of qualitative features about the risk (the number of deaths, for example, rather than the manner of death)?53 Why is risk commonly represented as the product of likelihood and severity? Like RA, CBA has been charged with focusing on outcomes that can be measured easily, which may not adequately reflect what people care about most. CBA represents individuals’ values by representing them as a single unit of measure, as reflected in monetized market choices, which critics hold tends to distort individuals’ values.54

When costs or benefits involve human health, for example, there is little agreement among economists about what standard should be used to establish the statistical value of a life year.55 There are similar disagreements about how to value environmental and other kinds of outcomes.56 Each of these decisions depends on value judgments, argue the critics, and may be shaped by the availability of information. CBA has also been charged with failing to account adequately for costs that will not surface for many years or that may affect only distant people or nonhuman forms of life.57 These problems suggest that CBA may distort or omit considerations important for public policy. Critics also maintain that RA and CBA address uncertainty poorly; how to appropriately respond to uncertainty may itself be a significant value question. In sum, critics believe that a failure to understand the normative assumptions in formal impact assessment mechanisms leads to distortions, including a failure to identify all outcomes worth assessing, an epistemological bias in what counts as evidence for outcomes, and errors in the assignment of weights to potential outcomes. These substantive criticisms feed misunderstanding and distrust about the policy-making process in which impact assessment is used. If RA and CBA incorporate values only quietly, as assumptions buried within technical and sometimes arcane terminology, then the public confusion and antipathy could be exacerbated. RA and CBA could be seen as arrogating to experts and closed-door discussions issues that are properly the domain of the overall public, and therefore as protecting the interests of the powerful. Many defenders of RA and CBA now recognize that these tools make normative assumptions—that the tools are not objective in the sense of being entirely “value-free.”58 Still, there can be debate about whether they incorporate values objectively—where “objective” can mean either that no one (“subjective”) value perspective is privileged above others or that only rational, justifiable values are given weight. Here, the rich literature on risk perception has provided grounds for recognizing both the need to consider the public’s views about risk thoughtfully, given the complexity of risk, and the need somehow to correct or refine the public’s views about risk, given the great difficulty humans have in thinking about risk clearly.59 Analogously, the complexity of the public’s perceptions of risk give grounds both for depend-


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ing on technical expertise for outcomes assessment and for actively engaging the public in some form of democratic deliberation about outcomes.60 Exposés of human foibles in comprehending risk can seem to suggest that the public’s views need more correction than respectful attention, and that experts are more to be listened to than the general public.61 If all risk perception depends at bottom on subjective perspectives, however, then balancing these competing assessments of the public’s risk perceptions might be preferable. Clarifying the credentials necessary to offer an “expert” opinion about possible outcomes may also be helpful. The second area of disagreement is about the content of the values that should figure in outcomes assessment. This disagreement often centers on a debate about whether to take a “proactionary” stance toward science and technology—that is, to limit restrictions on development and application and perhaps to provide financial and other support—or a “precautionary” stance—an idea that comes in a variety of formulations and flavors but centers on the idea that measures may be taken to avoid possible harmful outcomes even in the absence of conclusive scientific evidence that the harms will occur.62 A precautionary stance is thus an attempt to alter the burden of proof in scenarios involving uncertainty. Although many acknowledge that the central idea in precautionary positions has considerable intuitive appeal— it is often said to be captured by such maxims as “Look before you leap” or “Better safe than sorry”—the various attempts to articulate the stance as a formal principle have come under fierce criticism. Where risk assessment and cost-benefit analysis are seen as implausibly value-neutral and analytic, a precautionary position is seen as hopelessly vague and as grounded only on emotions and, in particular, on fear.63 Also, it may fail to understand that assessing outcomes inevitably involves risk-risk trade-offs, such that the risks of limiting or barring a project must also be considered alongside those of proceeding with it.64 Where CBA is seen as undercounting possible harms, precautionary positions are seen as dramatically overweighting them, to the point of being blatantly antiscience. Where CBA is thought to deal poorly with uncertainty, precautionary positions are thought to give so much weight to uncertainty that—because uncertainty abounds in all possible actions—a precautionary position can lead only to paralyzed inaction.65 In fact, different versions of a precautionary position can endorse varying degrees of precaution, and some versions spread the burden of proof.66 Also, some commentators have looked for compromise positions about the usefulness of the precautionary positions. In its report on policy-making for synthetic biology and other emerging technologies, for example, the PCSBI recommended a position of “prudent vigilance” as a middling stance between proactionary and precautionary positions.67 Still others have attempted S14

to modify the use of RA and CBA so as to be more responsive to the public’s concerns about outcomes.68 For example, Cass Sunstein, one of the best-known proponents of the cost-benefit paradigm, has proposed, in place of the precautionary principle, a limited and focused “anti-catastrophe principle” for projects that may bring about particularly dire risks or costs but in which the probability that those risks or costs will occur is highly uncertain.69 Articulating and examining the normative assumptions of formal impact assessment can contribute to this discussion. Reliance on RA and CBA is often thought to constitute a generally proactionary policy stance. Often, too, the characterization is mapped onto a distinction between U.S. and European approaches to science and technology, with the U.S. approach leaning toward proaction (via RA and CBA), and the European toward precaution. Yet this understanding may be mistaken. While Europe has favored a precautionary stance on some issues concerning biotechnologies, such as genetically modified crops, it has been markedly proactionary on other topics, such as construction of nuclear power plants, where the United States has been more cautious.70 Moreover, RA and CBA are employed in Europe as well as in the United States. The question arises, then, whether RA and CBA can in fact be implemented in ways that permit an explicitly precautionary position. If so, then the different results might be a consequence of making different normative assumptions. Similarly, it is unclear whether RA and CBA exemplify the “prudent vigilance” recommended by the PCSBI. The confusion here is partly that the notion of “prudent vigilance” is itself unclear. Although “prudent vigilance” suggests some degree of precaution, the PCSBI did not attempt to fit its recommendations into the existing literature on the precautionary principle, and although it said that evaluation of synthetic biology should be “ongoing,” it did not explain which evaluation processes are appropriate. Since it also did not call for significant constraints on the technology, critics were left with the impression that the PCSBI had endorsed a fundamentally proactionary policy stance.71 In short, there are several different relationships that RA and CBA are seen as having toward values: as being free of values, as objectively representing the public’s values, as hiding values and illicitly favoring science and technology, and possibly, at least on occasion, as making possible a “precautionary” or “prudently vigilant” stance. A lack of clarity about how RA and CBA represent the public’s values is connected to, and complicated by, the tensions between correcting and reflecting the public’s perceptions about outcomes and between relying on technical expertise to assess outcomes and engaging the public broadly in deliberation about outcomes. November-December 2014/ H A S T I N G S CE NTE R RE P O RT

Synthetic biology generates a kind of perfect storm for reasoning about potential benefits and harms. Attending to the philosophy of risk is vital for navigating through it. Disagreement and confusion about how values figure in outcomes evaluation is common across many industrial, medical, and environmental contexts, but it is particularly striking in synthetic biology.72 Partly this is because the PCSBI’s recommendation for prudent vigilance, a novel and explicitly value-laden formulation, complicated the debate about how values figure into outcomes evaluation. In addition, however, it is because the potential outcomes associated with synthetic biology are especially challenging to assess. The fundamental difficulties in identifying and assessing outcomes are particularly great with synthetic biology, given the scale and complexity of the possible applications, the uncertainty surrounding them, their possible misuses, and the great potential costs of not going forward with them. Also, there are the familiar problems about how mathematically to model the effect of delayed harms or benefits, given that the transformative effects of the technology might be fully realized only slowly. Also, the risks of synthetic biology rank high on the psychometric measures, such as lack of familiarity and controllability, associated

with extreme risk aversion.73 The fact that some of the most remarkable outcomes are fundamentally irreversible further reduces the sense of control. The sheer magnitude of the potential outcomes raises questions about how significance is determined for extreme risks and socially transformative benefits. The uncertainty associated with synthetic biology and its potential for social transformation also force questions about whether the public’s attitudes toward social change and uncertainty are themselves normative positions that could legitimately influence outcomes assessment. Finally, straightforwardly consequentialist concerns intersect with concerns that are often understood as nonconsequentialist, such as whether the distribution of benefits and harms will be just, whether the alteration of nature is intrinsically undesirable, or (alternatively) whether the advance of the human capacity to understand and improve the world is intrinsically morally desirable. In short, synthetic biology generates a kind of perfect storm for reasoning about potential benefits and harms, and attending to the philosophy of risk is vital for navigating through it.

IV. Distribution and Representation: Concerns about Justice

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he development of emerging technologies has by and large not been constrained by concerns about whether the technology will tend to promote just or unjust distributions of power and resources. Those questions have been thought to guide decisions about applications, not decisions about whether to advance the technology in question. The assumption has been that technological advance is beneficial to a country economically and sometimes militarily and that, overall, the possibilities for social benefit are increased when scientists have a very high degree of freedom to pursue whatever lines of work look most promising and interesting to them. Liberty is also often valued deeply for its own sake as well, providing another kind of consideration, also grounded in some conceptions of justice, for not interfering with the initial development of a technology. Questions about justice can, and we believe should, be asked not just about the applications but also about the very research and development of the technology. Research often poses potential harms and benefits that can be al-

located justly or unjustly. The development of synthetic organisms for the human microbiome might involve clinical trials that pose a safety risk to the trials’ subjects, for example. The development of synthetic organisms to produce fuel might pose a locally elevated environmental risk, particularly if the organisms were not kept in fully closed systems. Also, if the manner in which a technology is developed generates or constrains the range of eventual applications, then the development has consequences for whether the applications turn out to be just or unjust. If so, the development should be examined, and guided by a concern about justice, as much as the applications themselves. Concerns about synthetic biology and justice arise in a number of ways. First, there are concerns about the downstream consequences of the eventual applications. The case of biofuel exemplifies concerns of this sort. If fuel could be produced in an economically competitive way—by, let us suppose, E. coli that have been modified to incorporate metabolic pathways that convert glucose to acetyl-CoA, which can be used to produce ethanol and butanol (and


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other products)74—then there would be an economic incentive to produce very large quantities of glucose, perhaps in sugarcane plantations. The plantations would have to be located in very sunny places with very long growing seasons. Land that fits this description tends to be in developing countries. But then various worries arise. The plantations might be located on developed agricultural land, in which case they might undercut food production, or they might be carved out of undeveloped land, in which case they might contribute to environmental damage. Either way, the plantations would likely be owned by large corporations rather than large numbers of small farmers. They might provide some employment opportunities, but the track record of large plantations in economically poor parts of the world is not good: the jobs might well turn out to be very demanding, low-wage positions, with most of the plantations’ profits turned over to others. Second, there are concerns that synthetic biology might replace the means of livelihood of people in developing countries. This might be a particular concern, for example, with applications involving the production of smaller quantities of high-value chemicals such as flavorings or fragrances that are currently produced by farmers in developing countries. Third, concerns have arisen both from critics of synthetic biology and from within synthetic biology about ownership of and control over the technology. The worry is that a relatively small number of private entities, presumably located in the global North, will be able to claim patents on key aspects of the technology; perhaps there would be particularly influential corporate giants that would be largely able to dictate terms of use for the technology.75 But if the technology may have so much influence over the commonweal, argue critics, then ownership and control should be held in common. To critics from outside the field of synthetic biology, this means power to limit the technology; to those within the field who worry about corporate control, it means an open access intellectual property framework that promotes the democratization of the technology, which is needed to advance the technology’s development and perhaps is desirable in and of itself. Thus the case of DIYbio is not just one of the ways in which work on synthetic biology might occur; for some, it is also an ideal of a form of production worth promoting and defending. Finally, in addition to these concerns about how the risks and potential benefits will be distributed, justice has implications for how these concerns—and any of the other concerns raised about synthetic biology—will be addressed. Will the development of the technology be controlled mostly or only by those with financial or political power, or will the general public, which after all has an interest in the changes the technology might bring about, have a say? Somehow, critical perspectives and the perspectives of S16

those likely to be affected by the applications should contribute to these decisions. We return to this issue below in our section on deliberative democracy. The challenge for making headway on concerns about justice is partly just that the concerns are hard to get one’s head around. There are well-known practical and philosophical problems here. The practical problem is the difficulty mentioned earlier of predicting how a new technology will be used and what social impact it will have. If the technology might well turn out to be transformative, leading to entirely new social arrangements, then there may be very little to say up front about how it should be developed: even if we can identify many relevant problems of justice to attend to, we might not know enough about how the technology will bear on them to be able to weigh in authoritatively. Also, the multiple global concerns at stake may not all be aligned with each other: in principle, it is possible that a given application of synthetic biology to produce fuel could be beneficial for a developing country in some ways (perhaps providing opportunities for economic development and helping to stem the effects of climate change by providing a carbon-neutral way of producing fuel) yet harmful in other ways (replacing agriculture with sugarcane plantations, raising the country’s burden of environmental degradation). Perhaps, too, the very same application would have a different calculus in a neighboring country—a country whose socioeconomic patterns and susceptibility to the problems caused by climate change make it unlikely to realize the benefits that might be observed in the first country. The problem here is more or less the same problem as that confronting the analysis of risks and benefits, except that here we must consider the distribution of risks and benefits in the context of the history of uneven distributions and imbalances in power across the globe. The task is not to make judgments about whether a given application is just or unjust but to bring steady, careful attention to emerging applications so that, as they develop, their likely social consequences can be understood and shaped. This means creating a process for reaching judgments: enlarging the deliberation so that it includes a wide range of experts and stakeholders, and also breaking it down into manageable chunks by considering particular applications over a period of time, as research is carried out and the application takes shape. In addition to these practical uncertainties are philosophical difficulties, also well known, of settling on an account of the principles of justice that can help make substantive headway on the questions of justice that synthetic biology poses. Different conceptions of desert, equality, and rights point toward different resolutions. Even within a group of people who broadly agree on the principles of justice, the principles are likely to stand in tension, defense November-December 2014/ H A S T I N G S CE NTE R RE P O RT

Some countries would rather not be “Americanized.” But will it be possible for societies to opt out of a future defined by synthetic biology? of individual liberty conflicting with the desire to promote equality or advancement of the commonweal, for example. Exactly how to make those trade-offs, in specific cases, will not fall out of the theory in a clear and uncontested way. The disagreement within societies on any broad, theoretic attempt to articulate and rank-order these principles compounds the difficulties. And yet social policy on synthetic biology must be made not merely at a societal but also at an international level. How then to balance liberty to explore biology, experiment, innovate, and develop marketable products with an imperative to defend the interests of the least well off? A strategy often proposed in contemporary justice theory is to shift away from trying to articulate an overarching theory of justice and focus instead on identifying and deploying less theory-laden and less controversial claims. Perhaps there would be fairly broad agreement, for example, that we should strive to ensure that the worst off are not made still worse off.76 And though there is great disagreement about what constitutes a benefit, many theorists have noted that there is somewhat less dispute about what constitutes an evil. Yet one may worry that such minimal, greatest-common-denominator requirements will be too diffuse to provide meaningful guidance. The Nuffield Council’s 2011 report on the ethical issues of biofuels proposes a somewhat richer set of baseline requirements, many of which are relevant to a range of synthetic biology applications.77 Two of these requirements are meant to ensure that biofuels do not exacerbate global environmental problems: they must be sustainable and contribute to a net reduction in greenhouse gases. Three others bear more directly on questions of justice: human rights (including access to sufficient food and water, health rights, work rights, and land entitlements) should not be violated; labor should

be appropriately rewarded (through fair trade principles and recognition of intellectual property rights); and costs and benefits should be distributed equitably. At the same time, one may worry whether even these condensates—the residue of trying to boil away any overarching theoretic structures—will still make unwarranted yet important assumptions. Even the minimalist approach of striving to ensure that the economic condition of the worst off is not worsened allows that undeveloped countries will be developed: economic activities originating in other nations will tend to spread high technology and the cultural pathways that are associated with them, to some degree displacing or at least altering native traditions. But the simple fact of development can raise a question of justice; some countries would rather not be “Americanized,” and their sovereignty of culture may be at stake. Italy and France try to protect their small farms from the inroads of international agricultural trade. Similarly, perhaps people in some countries would want to protect subsistence farming or hunter-gatherer lifestyles. Yet can that question be articulated and treated in a way that would allow them to opt out of a future defined by synthetic biology? Greatest-common-denominator requirements also still leave many profoundly difficult trade-offs. The good of preserving a traditional culture may conflict with the good of economic development. Intellectual property rights may conflict with the goal of maximizing benefit to the least well off. The right to labor may seem to involve a trade-off with health care. The question, which is practical as much as philosophical, is how to conduct a debate about synthetic biology and justice. Perhaps, then, the overriding concern about justice is the fourth listed above—that of bringing additional voices to the decision-making.

V. Taking Deliberative Democracy Seriously

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n fact, that additional voices should somehow be brought to the table seems to follow from the discussion of all three broad kinds of concerns so far discussed. If some people find synthetic biology intrinsically troubling, those concerns need to be articulated and tested publicly before they are taken up in public policy; indeed, the very idea of taking up such concerns in public policy needs pub-

lic articulation and testing. Similarly, the evaluation of synthetic biology’s potential benefits and risks requires public input; we have called above for more consideration about whether and how values are part of impact assessment, and this inquiry also points toward public deliberation. The trade-offs described above between the distribution of knowledge and the control of potentially dangerous infor-


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mation also might be illuminated by public input. And as just shown, the questions of justice raised by synthetic biology require broad public input; indeed, getting appropriate input on all of the moral questions raised by synthetic biology is itself a matter of justice. Yet if we hope to bring additional voices into the decision-making, it is important to be clear about how that would be done. It is easy to talk airily about “engaging the public” or “informing the public.” If the public is genuinely to have input, however, some form of what is known as deliberative democracy is required. In this section, we walk through a few key elements in organizing deliberative democracy, including the challenges that must be addressed to make it work, so that calls by the PCSBI and others for public engagement are more than empty rhetoric. Deliberative democracy is often described as a particular way of making decisions that relies on a process of reasoned exchange in which participants listen to others as well as voice their own opinions.78 Some theories of democracy assume that the preferences of participants remain fixed; in contrast, proponents of deliberative democracy envision a process by which participants may change their minds.79 While deliberation may occur among relatively small and nonrepresentative groups of political actors, proponents of deliberative democracy almost always place an emphasis on creating a more inclusive process. Broader participation may support the goals of deliberation because a more inclusive process allows for a full range of views to be heard and is more likely to encourage the participants to rethink their original policy positions.80 Advocates for deliberative democracy are less clear about how broad participation needs to be, and there is often a tension between broader participation and effective deliberation. Arguments that promote the use of deliberative processes for making legislative or regulatory decisions often fall into two broad categories. First, a deliberative process will result in better policies than those produced through a more conventional decision-making process. Second, a deliberative process can produce outcomes that the public views as more legitimate. The idea that some form of deliberative democracy can lead to better policy decisions has its roots in Aristotle’s argument for governance by the multitude. Aristotle argued that “supreme power ought to be lodged with the many, rather than with those of better sort, who are few . . . for, as they are many, each person brings in his share of virtue and wisdom; and thus, coming together, they are like one man made up of a multitude, with many feet, many hands, and many intelligences.”81 Drawing on the experiences and perspectives of a greater number of people and groups can help policy-makers learn from past mistakes and identify new solutions to vexing problems.82 Creating S18

avenues for greater public participation in decisions about synthetic biology could help identify a broader range of benefits and risks to the people affected; in addition, the weights placed on those risks and benefits should reflect what is learned through the deliberative process. Greater Legitimacy and Trust in the Process

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s the PCSBI argued in its report, regulatory decisions that emerged from a more open and inclusive process should be considered more legitimate than those that emerge from closed decision-making processes.83 According to Jürgen Habermas and William Rehg, a constitutional state requires “that the administrative system, which is steered through the power code, be tied to the lawmaking communicative power and kept free of illegitimate interventions of social power,” and developing “a communicative power of this kind [requires] non-distorted communication.”84 Because deliberative democracy is supposed to involve a more inclusive decision-making process, there is a greater chance that those who are affected by the decision have an opportunity to influence it. It may also generate more legitimate decisions because of its emphasis on the exchange of reasons. “Minimalist” forms of democratic decision-making, which rely on the aggregation of votes, often assume that citizens have fixed preferences that are in competition, and that policy-making involves bargaining within a political marketplace to determine how best to aggregate individual interests.85 In contrast, deliberative models of policy-making call for decisions to be made by discussion among free and equal citizens.86 Deliberative models also assume that this exchange may lead people to change their initial preferences, by learning from others and gaining a greater appreciation of different points of view.87 This highlights an important limitation of deliberative democracy that could limit its applications to synthetic biology. If moral conflict is so deep that participants are unwilling to consider other viewpoints, as is sometimes the case with religious or cultural views about the relationship between humans and nature, then deliberation may not be sufficient to reach a decision.88 Under these circumstances, deliberation may clarify the nature of the moral disagreement, but society may have to rely on voting and other forms of aggregative democracy to reach a decision. Even if deliberation cannot always resolve conflict, it can be useful by clarifying the basis for public decisions. A central goal of deliberative democracy is for “citizens and officials to justify public policy by giving reasons that can be accepted by those who are bound by it.”89 As Rebecca Dresser explains, “[B]ioethics is predicated on the premise that public and patient values matter—that physicians, scientists, and government officials should not completely November-December 2014/ H A S T I N G S CE NTE R RE P O RT

Proponents of deliberative democracy envision a process by which participants may change their minds. control how medicine and research are practiced.”90 In contrast, if the public believes that deliberative activities are designed to appease them or are biased in favor of a particular set of actors, then the efforts can undermine, rather than improve, public trust.91 Challenges of Creating a Deliberative Process

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he PCSBI called for “deliberative engagement with a wide variety of sources, including scientists, engineers, faith-based and secular ethicists, and others who voiced, as expected, sometimes conflicting views on the science, ethics, and social issues surrounding synthetic biology.”92 Yet though the aspiration to be inclusive is clear, the recommendation leaves some vital questions unanswered. What specific criteria should the federal government use when identifying participants in such a deliberative process? Should participants reflect ethnic, gender, geographic, income, racial, or sexual orientation differences in the general public? Should the government give disproportionate voice to people who may be directly affected by developments in synthetic biology, or should it give equal voice to other citizens because the decisions made are likely to affect everyone in society? Traditional regulatory approaches tend to focus on “stakeholders” with a direct interest in the policy decision, but efforts to use some form of deliberative democracy usually involve broader representation from the general public. This may take several forms, including a randomly selected group of citizens to participate in a “citizens’ jury,” which meets over several days to deliberate about a specific policy, or a “citizens’ council,” which meets routinely to act as a sounding board for a government agency.93 Deliberative polling draws on even larger samples of citizens and combines traditional public opinion poll techniques with small group discussions and information from competing experts so that the poll reflects aspects of deliberation.94 Successful deliberations, in which success is usually measured in terms of whether the process was inclusive and fair or whether participants viewed the process as legitimate,95 may also take place among a more limited set of participants who meet regularly to advise policy-makers. In Connecticut, the state General Assembly created a Medicaid Managed Care Council to oversee the implementation of Medicaid reform in that state. The council members included members of the General Assembly, several representatives from relevant

public agencies, managed care organizations with contracts from the state, a host of nongovernmental organizations, and Medicaid clients. Despite the fact that it does not have any regulatory authority, the council has helped to identify problems and solutions that the state may not have identified or pursued through more traditional regulatory methods.96 There is always a concern that efforts to bring together scientific experts and members of the lay public will not be sufficiently balanced because members of the public will defer to “experts.” Even among lay members of such groups, people with “higher-status jobs, greater education, and higher income talk more and are more likely to be (often incorrectly) perceived as more accurate.”97 Power differentials pervade real-world politics, often affect whether subordinate groups feel comfortable voicing their concerns, and sometimes distort the subordinated group’s sense of its interests and capacities. Marginalized groups tend to acquiesce to the more powerful, which can limit the ability of the public to lobby effectively for policy change.98 This challenge is exacerbated by the fact that scientists may take a dim view of the public and its capacity to understand science, believing instead that scientists should enjoy a privileged position in all debates about science policy.99 This view, however, has been challenged by others in the scientific community.100 Professional advocates who speak on behalf of the public play a vital role in incorporating the public’s views into policy-making, and their participation in a deliberative process can help address the power gap between scientific experts and the public, but relying on them highlights the importance of understanding the extent to which they genuinely represent the public. It is often difficult to assess whether people and organizations that claim to represent particular interests, particularly those who are routinely excluded from the policy-making process, do so faithfully. The Tension between Broader Participation and the Quality of Deliberation

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t is important that, when designing a deliberation, the government consider whether the constellation of groups that will participate represents the range of perspectives in the general public. At the same time, it is important to acknowledge that there is a tension between involving more participants and encouraging regular interaction among


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relatively small groups. It is difficult to arrange a deliberation among a large number of participants because it is less likely that all participants will make a meaningful contribution to the discussion. Robert Dahl and Edward Tufte argue convincingly that smaller communities are more likely to resolve conflicts through a more informal process of reason-giving and arguing, while larger communities are more likely to rely on formal rules and processes.101 As a result, as John Parkinson explains, “deliberative participation by all those affected by collective decision-making is extremely implausible,”102 and identifying an appropriate range of representatives is likely to be crucial. The development of synthetic biofuels, for example, could affect an enormous number of people. A deliberative process would need to identify an appropriate range of perspectives while keeping the number of participants manageable. Furthermore, because the impact of synthetic organisms that are released into the environment would affect people outside the boundaries of the United States, or any other nation-state, procedural justice may require some form of global participation.103 Finally, a public deliberation about synthetic biology requires that participants have access to “balanced, factual information that improves participants’ knowledge of the issue.”104 Deliberation depends on “public judgment” based on knowledge of the problem and information about the consequences “associated with alternative policies.”105 The PCSBI recognized this when it urged the use of “clear and accurate language” and avoiding hyperbolic claims like the idea that synthetic biologists are “creating life.” Along with the need for accurate descriptions of synthetic biology and the consequences of alternative regulatory approaches, the materials presented to participants in a deliberation should incorporate lessons from behavioral economics and address potential framing effects that may influence the response of individuals to different scenarios.106 In their classic work on framing, Amos Tversky and Daniel Kahneman explained that the way alternatives are described or “framed” can change how people make decisions.107 In 1981, they presented the results of an experiment in which people were asked to select one of two public health programs that would combat a new infectious disease that is expected to result in 600 deaths. The participants were asked to select one of two alternatives: “If Program A is adopted, 200 people will be saved. If Program B is adopted, there is 1/3 probability that 600 people will be saved, and 2/3 probability that no people will be saved. Which of the two programs would you favor?” Statistically, the two programs would be expected to produce the same results, but 72 percent of the participants chose the first alternative because they wanted to make sure that they could be certain that 200 people would be saved and option B was framed as taking a risk. S20

Next, Tversky and Kahneman described two additional alternatives: “If Program C is adopted 400 people will die. If Program D is adopted there is 1/3 probability that nobody will die, and 2/3 probability that 600 people will die. Which of the two programs would you favor?” The great majority—78 percent—selected alternative D, even though the outcomes of C and D are identical. In the second experiment, unlike the first, then, people selected the risk-taking alternative. Tversky and Kahneman argued that this difference occurred because the first problem was described in terms of the number of lives saved and the second was framed in terms of lives lost. They concluded that people have more powerful emotional reactions to losses than gains. This finding has been replicated by behavioral economists repeatedly.108 Because there are scientific and political disputes about the nature of synthetic biology and the extent to which its applications may generate benefits and risks, this requirement may be particularly challenging. Who should be responsible for developing these materials? How will they be vetted? How will the government frame the material it shares with participants, particularly when faced with scientific ambiguity or political dispute about how to define or weigh benefits and risks? One solution to the problem described above is for deliberations to present alternatives in terms of losses and gains to better understand whether the results of the deliberation reflect underlying values or are an artifact of framing. This alternative highlights the fact that a successful deliberation requires significant planning and resources. Yet while this process may appear to be less efficient than a traditional regulatory process that is less open to public participation, the benefits of providing opportunities for public deliberation may outweigh the costs if it helps to avoid the prolonged legal or political battles often associated with regulation.109 Is Successful Public Deliberation Possible?

A

ddressing concerns about power, structure, and the quality of information in a public deliberation is difficult, but a deliberative process that is attentive to them is more likely to be accepted by the public as legitimate. There is a growing body of evidence that these challenges can be met. During the 1990s, there was an extraordinary growth in the number of organizations organizing deliberative forums in the United States and around the world. A number of successes have been achieved with the Problem Formulation and Options Assessment methodology, which was designed to encourage deliberation about the regulation of nanotechnology and genetically engineered organisms.110 PFOA involves interactive meetings between scientists and a variety of stakeholders in order to bring social values into the evaluation and regulation of techNovember-December 2014/ H A S T I N G S CE NTE R RE P O RT

Deliberation cannot always resolve conflict, but it could still be useful in clarifying the basis for public decisions about synthetic biology. nologies that pose very uncertain potential benefits and risks. The process strives to be “transparent, inclusive and informed by the best available science,” including a clear articulation of the assumption on which science is based and an acknowledgement of any known uncertainties.111 To date, it has been used in a diverse set of countries, including Kenya, Brazil and Malaysia—and it has also been used to facilitate successful deliberations among representatives from multiple countries. Organizing a successful deliberation requires being explicit about trade-offs. For example, there is broad consensus that deliberation must involve members of all affected communities, but disagreement about whether that requirement is best achieved by purposefully selecting

members of these communities or trying to identify people who are “empowered” to represent particular groups. Individuals from nongovernmental organizations often play a crucial role in representing the voices of poor and vulnerable populations, but they are rarely elected to these positions by people from the groups they claim to represent. Despite these problems, limiting the participation of such groups might significantly reduce the probability of considering the perspectives of people who may be less able to participate directly in a public deliberation. Rather than allowing the perfect to be the enemy of the good, we should emphasize transparency and be explicit about the nature of the organizations and the basis of their claims to represent a particular social group or perspective.

VI. Upstream Ethics: How to Make an Emerging Biotechnology Turn Out Well

T

he position we’ve come to is that objections to synthetic biology are morally significant, complex, and profound yet would be decisive only for particular applications. There are also significant, complex, and profound reasons to let the technology unfold, and in general, the research and the applications that can be envisioned in the near term seem permissible. We have discussed three broad categories of concerns:

cussions of the technology. However, synthetic biology presents some intriguing and some very alarming possibilities, which call for very careful study and monitoring. That process requires transparency about the research and interdisciplinarity among those engaged to evaluate it; it should begin early in research and continue after any application; and it should be flexible enough to respond to changes in the technology.

• The human relationship to nature. Anyone who is generally concerned about the human relationship to nature has reason to ponder the influence of synthetic biology on that relationship. The technology does not disprove any special philosophical or religious conceptions of life, however. Given the limits of the technology—that only comparatively simple organisms can currently be modified and that the modifications are still rather limited— many applications do not appear to drive any meaningful change in the human relationship to nature.

• Concerns about justice. Not only should applications of synthetic biology have a just distribution of harms and benefits, but also, ideally, research and development in synthetic biology should be the regulated and funded with an eye to promoting just distributions of harms and benefits. There are no widely accepted substantive guidelines for discussing the allocation of harms and benefits of synthetic biology, much less about potential harms and benefits. Possibly, the discussion can be facilitated by focusing on potential harms, and certainly, it ought in some way to include the perspectives of those likely to be affected by the applications.

• Concerns about risks and potential benefits. Very possibly, both the potential harms and the potential benefits of synthetic biology are overstated in most dis-


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These concerns are broad substantive requirements for the development and application of synthetic biology. However, final recommendations about synthetic biology are not yet possible. Final assessments are not possible even within the four somewhat narrower categories of cases that we used to highlight and examine the substantive concerns. The most that can be said is that some kinds of cases call for particularly careful scrutiny: applications that would involve deliberate release of organisms into natural environments or into the human microbiome, for example, require particularly detailed examination of their possible effects. Applications to develop new methods of producing valuable chemicals highlight some questions about justice—about the range of a scientist’s or private corporation’s liberty and responsibility, about the consequences of creating an industry that would be dependent on inputs produced by plantations, about potential loss of work opportunities in developing countries, about intellectual property rights, and about whether societies have a right to try to protect traditional cultures against modernization. The capacity to develop innovative applications in DIYBio settings raises questions about whether centralized monitoring and guidance will be adequate for synthetic biology. Since a final evaluation of synthetic biology is not possible, we must focus instead on the conditions and processes for evaluating synthetic biology. These broad substantive considerations point toward several recommendations about process: • For public deliberation. All of the concerns above must be given content through a process that substantively engages the public—a process that will include public education but also allow public input into the development and use of the technology and that, as the Nuffield Council has argued, will make a special effort to attend to easily overlooked perspectives, values, and concerns. Nearly all commentators are agreed on the need for public deliberation. To ensure that public deliberation is meaningful, however, there must be more attention given to what public deliberation means and how it can be practically carried out. • For good information. New Directions issued a call for accuracy, with a special caution about possibly overblown and misleading language such as “playing God.” This advice also holds for synthetic biology’s proponents, whose claims about the benefits of synthetic biology move very quickly to the grandest, best conceivable outcome. (It is our sense that strongly worded claims about what genetic alteration of organisms can accomplish, and about what it means, tend to meet strongly worded objections.) It is also important to try to be clear about what concerns are on the table. Most concerns about synthetic biology S22

are ostensibly about the risks for human beings and the distribution of the risks, but the language in which those concerns are expressed sometimes implicitly conveys a dislike of the very idea of synthetic biology. This may be an effective way of encouraging public distrust of the technology, but it is not the best way of articulating the moral concerns. The need for good information also applies to technical information about synthetic biology applications—information about which organisms have been developed, how they have been modified, and what the possible effects of the modifications are. This information needs to be not only accurate but also as complete as possible in order to facilitate research into possible risks and in order to make public discussion of the application possible. • For iterative analysis. One point shared by New Directions, “The Principles,” and by many other reports on synthetic biology is a methodological assumption about how ethical analysis can bear on technology development. This is that, in advance of the full development of an emerging technology, we can and should try to think about how the development might turn out, and we should try to make some decisions early on in the development so as to make the technology turn out one way rather than another—or even to halt its development altogether. If a technology is genuinely transformative, then we may not be in a position to make genuinely anticipatory decisions about it, but failing that, we can aim to monitor the technology and try to respond to it as it unfolds and as potential applications come into view. Taking an iterative approach is also necessary to think appropriately about the moral goals themselves. Some of the key concepts in play—nature, justice, and risk and benefit—cannot be given incontrovertible definitions but must rather be regularly refined and perhaps worked out afresh. Regularly returning to these topics can also help ensure that voices that should be part of the deliberation over these matters are not ignored. • For professional self-monitoring. The concerns about synthetic biology probably cannot be addressed by relying strictly on outside entities to monitor and direct the technology’s development. It would be convenient if the synthesis of potentially dangerous or destructive microbes could be undertaken only by very large, well-funded, and relatively conspicuous laboratories, but in fact, relatively small laboratories, capable of operating more easily under the radar, will be able to do this kind of work. Monitoring this activity will be easier if the field of synthetic biology is characterized by a culture of responsibility and selfregulation, as the PCSBI commission and others have November-December 2014/ H A S T I N G S CE NTE R RE P O RT

recommended. Whether people within synthetic biology can be enlisted to help to bring about just distributions of risks and benefits—or should even be responsible for aiming at those outcomes—is a still more complicated question. However, if we want this new mode of production to go better than older modes did, enlisting those who are actually pushing it forward may be essential.

The substantive concerns also point to a further set of questions. In carrying the debate forward to these issues, however, we would also in some ways carry it back, for some of these further questions are even more fundamental. • Public policy and intrinsic value. What sort of stance should government in a liberal state aim to take toward moral views about the intrinsic worth or disvalue of genetic alteration of organisms? Should it, and can it, aim for neutrality on such views? If a liberal government may formulate policy that in some way actively supports such views, how far may it go in offering support, and how can we decide how much support to offer? To what degree, for example, should the strength of public support for a given view determine the strength of the support that government may provide? • Ethics of knowledge. Are there circumstances in which potentially dangerous knowledge should not be produced and disseminated? There is a very strong presumption in science to permit scientists to pursue their interests and to publish the results of their research. Nuclear physics famously raised this question in the twentieth century, but the fact that much of the research required governmental infrastructure helped make it relatively easy to control the generation and dissemination of knowledge. Synthetic biology, which provides the ability to create and refine microbial pathogens and to do so in fairly small and inexpensive labs, raises the question in a more difficult form. • Values and impact assessment. The assessment of risks, costs, and benefits often appears to be a technical enterprise that should be delegated to subject matter experts and should aim for a kind of neutrality about values. Much scholarship now calls this view into question: claims about what counts as a risk or benefit and how a risk is to measured, weighed, and discounted are matters of value. These contrasting claims warrant further examination. A further question is about how values are appropriately made part of impact assessment. To what degree, for example, should the public’s views about precaution be incorporated into impact assessment?

The development of synthetic organisms, the uses to which they can be put, and the social, public health, and environmental impact of those uses are not only not yet fully known but are also not yet fully knowable; we don’t yet know and cannot yet know quite where the technology will lead. What is needed now is an established social mechanism for evaluating the possible outcomes of synthetic biology, incorporating iterative investigation by individuals who are expert in the technical issues at stake—from national security to public health to ecology—combined with meaningful modes of engaging the public. References

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