Ethical and Safety Considerations in Synthetic Biology

An Introduction

Our university iGEM team are pioneering the first truly synthetic biology project here at Aberdeen; previously genetic manipulation projects have simply involved expressing, or overexpressing, a single gene. We are the first researchers to attempt to assemble a biological circuit, by combining components to generate an emergent property.

Before our lab work commenced, a few safety and ethical issues had to be considered. We were required to submit an application for permission to the local University of Aberdeen Advisory Committee of Genetic Manipulation (ACGM), the outcome of which can be seen in the document below.

As you may recall, the aim of our project was to create a bacterial picoplumber, capable of detecting and mending broken pipes. This required us to design three main modules, namely the AND Gate, the Quorum sensing device and the Latch. The AND gate ensured that expression of our two component glue commenced only in the presence of IPTG, released from the breach, and once a threshold population density was reached. The quorum sensing module was necessary in order for the e.coli to communicate and sense this threshold density and the latch ultimately induced timed cell-lysis, in response to the AND gate being switched into the ON state.

An emergent concern of the committee was the potential danger to an individual under the circumstance that our lysyl oxidase expressing e.coli be accidentally ingested, and subsequently replicate to high levels in the gut. In response to this issue we highlighted the theoretical ability of our system to self-lyse, once a critical population density is reached. This response can be seen in the section entitled ‘mitigation for potential from harm’.

We were, therefore, granted permission to commence our project under the proposed constraints: we were required to prove, with submitted experimental evidence, that the automatic holin-based cell lysis system worked, prior to expressing our two component biological glue (tropoelastin and lysyl oxidase components).

You can see the proposal document that we submitted to our Institute's Genetic Manipulation Advisory Group (GMAG) Committee here. This body reviews applications to manipulate genes at the University of Aberdeen, and issues approval for such projects once they have been assessed for risk. In the linked document, the section dealing with 'Mitigation of potential for harm' is highlighted yellow, and describes the precautions that were adopted in carrying out a synthetic biology project where the assembled genetic circuit was expected to exhibit emergent properties.

Ethics in Synthetic Biology

Ethics are a substantial part of how we perceive ourselves and our society. ‘Making an ethical choice depends on how we imagine ourselves, what we admire, how we are willing to be admired, what we are prepared to say we admire.’ (Saul, 2001). What then, are the ethics of synthetic biology? Perhaps we need to start even further back and really agree on what synthetic biology is, as many, even arguably within the field are still undecided, despite the term being first introduced by Szybalski three and a half decades ago. (Szybalski, 1974 ) While ethics are obviously a matter of personal conviction, to what extent do they feature in the possibilities that may arise from the field? What ethical considerations do people feel important in considering the future of synthetic biological work? While not the core of our remit, it is indisputable that our ethics played a role in conceiving and executing a project such as Picoplumber. In such a cutting edge area of research it is important to gain an understanding of the range of thoughts on synthetic biology in an ethical context;

“Although some form of regulation is needed, state regulation would be of limited use and purpose, as it would be more subject to party politics and party ideologies. A transnational body could be better placed to ensure maintenance of global standards in a world with evermore multinational industries. I feel that synthetic biology’s merit will remain context based, work on bacterium or plants in terms of agriculture and relieving famine or poverty will be undoubtedly a good thing, but I don’t believe cloning humans would be a good idea, if only due to the overpopulation problem we already face”
Sarah, 29, Immunologist

“I think there are limits on what I would apply Synthetic Biology practises to. I think extensive modification of mammalian cultures would become a little too ‘Gattaca’ for me. There are many guidelines already in place, particularly in working with animals that I feel comply well with my own feelings working with them. Many people are scared of change and unaware of the technicalities involved, but we needn’t dismiss their concerns as merely irrational. I think the problem has been that a few bad cases have led to people generalizing an entire industry/area of research. Greater levels of addressing these fears and educating people would be the key, but I feel the media is more negative than positive in this. Ethics is already a big consideration of any research project currently and an ethics committee rules on a great many studies, particularly those concern with genetic work. Regulation should be at a national level so the federal taxpayers know that such work is at the consent of the voters”
Phuong, 24, Biomedical Science

“It is interesting as it has raised questions that humans have never had to face before, however I feel you can’t just treat ‘ethics’ as a separate issue and ‘science’ or ‘GM’ as inexorable processes. All these things are rooted with the people who created them and influenced how the research worked, and everyone is working within a framework of ethics all the time, whether others agree or not. As a general principle, I see these things as tools, not good or bad, though they can be used for both. So our ethics must come in how we live our lives and use these tools every day. Also generally, there needs to be a greater democratisation of the decision making around these things, and better attempts to explain them to people who have a right to know- which is everybody. However, I am pro GM because I believe dissent towards it is rooted mainly in non-specific, self-justifying ideas about what is ‘natural’, rather than understanding the issue. But that doesn’t make me pro Monsanto or companies that lie about the content of their foods. I feel most medical advances can only improve things- however there must be a lively and open debate about when we should ‘fix the person’ or when we should ‘fix the world’. How far we should go with experiments is something that it is more important there is debate about than ever finding answers. Synthetic biologists and the companies they work for should have the ethical position of being very careful with what they let out into/push onto the world, and many would argue that they have not yet proved to be. And a very important part of ethics is not selling your results to the highest bidder, something which I do feel strongly about.”
Jenni, 20, Riding Instructor

“While there are a myriad of different angles and personal choices, projects should retain a sense of context and not rush blindly forwards, committing errors comparable to the ecological disaster the introduction of the Cane Toad was to Australia for instance.”
Hannah, 28, Virologist

“I think the technology is exciting that will undoubtedly reveal a lot, but that it will have to be correctly policed. I understand the desire for self reviewed control, but it is I think limited. I think public perception of this work has improved, in part thanks to scientists engaging with the public more. I have found that working with viruses, people sometimes make judgements, but many don’t find the idea so scary anymore once explained. I think the media sometimes oversimplifies things which can cause knee-jerk reactions. I don’t have any problems at all with creating artificial life, although I would have reservations about work involving virulent pathogens, particularly linked to military establishments.”
Phil, 29, Immunologist

“I feel that like every other industry the majority who will doubtless make sound decisions will always be overshadowed by a few irresponsible individuals. Work will have to be guided by regulation to be for social benefits, not for example military ones. Just because one can doesn’t mean one should.”
Steve, 31, IT Engineer

“I definitely think that there should be research in this field. There will no doubt have to be some specialized regulation to deal with the unique situations that synthetic biology will create. My experience with ethics boards for our work suggests that they are not dynamic enough to cover all the different areas of research and should perhaps work with those with specific area expertise in making their judgments. I understand patents have caused problems in many areas, but on the other hand private investment needs some incentive if it is expect to invest. Also, there will need to large scale, umbrella organisation to control it, consisting of a mix of researcher and others from legal professions and civil society groups, to counter that those in research may become blinded by their goals. I think that like global warming, this area may be full of people taking polemic, extreme positions, something that will only be made worse by media sensationalism. I don’t think people are stupid as such, they just don’t get access to real information. This problem is made worse by experts dismissing peoples concerns out of hand. It isn’t productive and I think scientists have to take some responsibility for the public perception of this kind of work.”
Judy, 27, Public Health

“The ethics depend on what you’re working with, if bacteria then what species? And of course the purpose is key. There also has to be a greater dissemination of knowledge, working with H.I.V. proteins, like I do, is actually largely harmless, but just the mention of it makes people outside this work uncomfortable. Any regulation of the field would have to try to maintain an even playing field, as everyone needs funding and such economic incentives can lead to neglecting controls in the name of competition. Everyone has their own ethics and a right to say and select what they want. Often, I think those with a vested interest may marginalize dissent. However I also think that people have to be more open to accepting authoritative sources for information on a particular area of research.”
Steve, 24, Molecular Biologist

“It strikes me as perhaps showing a tendency towards impatience and a desire to circumnavigate what I feel is the necessary incremental nature of concept development into a final product. While some people might have liked if we had just spat out the Porsche 911 at the start of the 20th century without the decades of development and tweaking and Morris Minors, we may have just killed much of the country in one (very) swift move had a Porsche been the first car out on the road. Are not the “mistakes” and sustained time to create improvements and corrections in fact fundamental to the triumph of the final product? To the pride it inspires? I also wonder about the idea of the “individual researcher” engineering these things undermines and marginalizes the teamwork of generations – friends, family and neighbours that are represented in the traditional “genetic engineering” of breeding, co-operative effort that resulted in the myriad of breeds that are of use to us today. Perhaps the ability to make whatever we want, exactly how we want it, whenever we want it underestimates the glory of a truly beautiful disaster.”
Teresa, 24, Riding Instructor

“Scientific pursuit is an end in and of itself. The vast majority of objections to this kind of work stem from irrational fears and high handed moralizing”
Pete, 38, Molecular Biologist

“While there is a lot of ethically centred regulation and legislation in biological study, there will doubtlessly need to be some more, tailored to the particulars of synthetic biology. Local states would be worse than useless in dealing with regulation; any ideas would be lost in a mass of bureaucracy. Hospitals and Institutes would be best to operate on personal guidelines, while complying with a national set of legislation. I think that ethics boards are often unsuited for a project remit. A solution could be an empty seat on an ethics board to be filled by a specialist in the area the work covers to contribute their expertise to an issue. An example would be a recent project of mine concerning public health on social networking sites and I think that none of the members of the ethics board were suited to grasping the particulars of these forms of interaction, which did to some extent impede our work. That said, I don’t think science should be controlled by public opinion. Most people don’t understand but subsequently form opinions, making working with the “general public” quite difficult at times. There is a great level of media hype and misinformation, driven by profit rather than a desire to tell the facts of an issue. These fears also are present and inflated by popular culture, such as constant sci-fi dystopias which must at some level permeate individual’s feelings about many new areas of research. However, there are some things in the industry that I feel are beyond what I’d call ethical. Australian companies going to third world countries to do research they wouldn’t get permission to do here for example. Another would be a recent thing here where a group wanted to recreate the polio virus and when rejected, kicked up a fuss about ‘violation of scientific goals’ which I feel is deluded nonsense. Such research should always have a purpose beyond the design remit and be driven by a sociological context than privatised motivation or profit.”
Katie, 23, Public Health

The above are a selection of thoughts on Synthetic Biology from people from a range of backgrounds. There are certain recurrent themes that arise from their contributions. First Synthetic Biology is currently very much operating in the shadow thrown by Genetic Engineering and the debates it sparked in the 1980’s. This has the benefit of interesting and engaging many people from both scientific and non-scientific areas as well as covering a lot of ground in laying foundations for debates on synthetic biology, though perhaps not as much has been established in public acceptance of such work as scientists could wish. This brings up the negative side of this inheritance. Many issues that plagued research in the past have been attached to synthetic biology (perhaps in part, as one person I asked about ethics mentioned, because of the unfortunate working title for the field) and in asking about its ethics, one has to make immediately clear that no race of cloned super humans is even on the horizon. The other clear outcome of people’s opinions is that many feel some form of regulation is needed, above and beyond that of ‘professional self-regulation’ (Balmer, 2008), many agreed with the sentiments that self regulation would of course be a factor in synthetic biology regulation but not to the extent that it will ‘necessarily displace traditional interventions based on regulation, legislation and treaties’ (Maurer et al, 2006). That said there was some disparity between respondents on the scale and style of regulation, whether based on institutions, nations or even international regulatory bodies, although one idea raised in the report by Maurer, Lucas and Terrell was that as well as an ethics advisory committee, synthetic biologists could receive advice from ‘an Ethics Hotline’ which has to be met with scepticism as to the benefit, use and serious function that that it could be expected to play. There is already in fact a great level of legislation in place concerning GMOs, such as the Recombinant DNA Advisory Committee (RAC) created by the National Institute of Health (NIH) introduced in 1976 with a number of guidelines creating thorough risk assessments for any genetic manipulation. Indeed ‘many scientists considered the NIH guidelines overly restrictive when they were first introduced, but over the past thirty years, the guidelines have been gradually evolved in response to experience’ (Tucker, 2006). As with the initial explosion of genetic techniques in the past, Synthetic Biology may be best served by an initial regulatory approach which might even run the risk of being overbearing with an understanding to evolve the system as research develops and for “good behaviour”. Safety measures like techniques of making genetically engineered organisms less likely to survive independently, such as relying on nutrients not found in large (if any) quantities in an environment have no doubt contributed to the safety record of recombinant DNA experiments, creating safety nets to help prevent even accidental release causing a significant problem. Even if the original NIH restrictions were unpopular with many scientists, the subsequent relaxation of many guidelines has not been popular with many civil society organisations such as the now defunct Sunshine Project, an anti-bioweapons NGO who were fierce critics of the American National Science Advisory Board for Biosecurity (NSABB) claiming their recommendations were not for safe control but ‘will instead assault regulation of a wide range of biodefense and biotech risk’ (Balmer, 2008). Another staunch critic is the Action Group on Erosion, Technology and Concentration (ETC) who have made a range of criticisms of the companies involved in synthetic biology and of the area in general, some of which will be looked at it more detail later. Ambiguous results of potential unintended side-effects of previous genetic work such as Bt-corn (so called for having been transformed with genetic material from Bacillus thuringiensis) (Losey et al, 1999) (Flachowsky et al, 2005) has no doubt also played a role in any potential mistrust of synthetic biology.

Some of those specific areas of concern regarding synthetic biology are;

Bioterrorism

A popular concept is the fear of “Bioterrorism” that has stoked much concern, for example, a short white paper released by the U.S. C.I.A. in November, 2003 concluded ‘Growing understanding of the complex biochemical pathways that underlie life processes has the potential to enable a class of new, more virulent biological agents engineered to attack distinct biochemical pathways and elicit specific effects’ (Tucker, 2006). The report also mentioned that some ‘engineered biological agents could be worse than any disease known to man’ (Balmer, 2008). The report went on to recommend a closer working relationship between intelligence services and the biological sciences community. Although the more in depth look at the threat of bioterrorism by Tucker and Zilinskas stated ‘At present, the primary threat of misuse appears to come from state-level biological warfare programs’ (Tucker, 2006), they went on to outline the two most likely forms of misuse as coming from a ‘lone operator’, compared to Theodore Kaczynski. They outline the lone operator as one of ‘a few individuals with access to laboratory equipment and supplies who are highly intelligent and well-trained but also deeply disgruntled, have sociopathic tendencies, or wish to prove something to the world’. Though the potential is limited at the moment, in part because of the new nature of the field but also that biological weapons are not that easy to manufacture and distribute. Not only has the infectious agent to be created but ‘a complex system consisting of (1) a supply of pathogen, either powdered in the form of a wet slurry or dried and milled into a dry powder; (2) a complex “formulation of chemical additives that is mixed with the agent to stabilize it and preserve its infectivity and virulence during storage; (3) a container to store and transport the formulated agent; and (4) an efficient dispersal mechanism to disseminate the formulated agent as a fine-particle aerosol that can infect the targeted personnel through the lungs. Finally the aerosol cloud must be released under optimal atmospheric and meteorological conditions if it is to inflict casualties over a large are’ (Tucker, 2006). These factors would prove difficult for even the most intelligent sociopath trained in synthetic biology; it would be even more difficult for the second source of bioterrorism identified – the ‘biohacker’. Analogous to the computer hacker, the media and to a lesser extent academia stoke fears of what these “biopunks” or the Open Wetware or DIY Biology movement may do. Tucker and Zilinskas describe the ‘biohacker’ as ‘an individual who does not necessarily have malicious intent but seeks to create bioengineered organisms out of curiosity or to demonstrate his technical prowess—a common motivation of many designers of computer viruses. The reagents and tools used in synthetic biology will eventually be converted into commercial kits, making it easier for biohackers to acquire them. Moreover, as synthetic-biology training becomes increasingly available to students at the college and possibly even high-school levels, a “hacker culture” may emerge, increasing the risk of reckless or malevolent experimentation.’ So to conclude, despite their earlier assertion about state biological warfare programs, the main threats of bioterrorism are sociopathic loners and irresponsible students who don’t know any better. A demonstration of how there is already ample legislation allowing authorities to act against suspected individuals, as well as some indication of the level of competence and situational awareness available to the enforcers of these laws came from the Steven Kurtz case (CAE Defense Fund, 2009). Of course the threat of bioterrorism is real, however given that the 2002 announcement of a successful synthesis of polio virus from oligonucleotides received from a commercial supplier based on the viral genome acquired from the internet by Dr Wimmer (Josefson, 2002), (Tucker, 2006) and (Balmer, 2008), given that that research was funded by $3m (Josefson, 2002), from the Defence Advanced Research Projects Agency (DARPA), who along with the Departments of Defense (DoD) and Energy (DoE) have injected ‘significant’ amounts of money into the field, including $3 million from the DoD to Dr Venter’s Institute for Biological Energy Alternatives. DARPA are also said to be particularly interested in DNA computing. (Bhutkar, 2005). Given that the Biological and Toxin Weapons Convention (BWC), which bans development, production, stockpiling and transfer of “microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic protective or other peaceful means” was undermined by the non compulsory nature of the convention, that in the Fifth Review Conference in 2001, the United States suspended the review, claiming a threat to national security from inspections and a threat to economic competition (the treaty unusually was also binding to private parties within signatory states) (U.N., 2001) The result of this was a dismissal of the Ad Hoc Group of experts, ‘no binding protocol would be agreed upon and further talks would only concern a non-binding framework’ (de Jonge, 2006). Given that British Defence Science Advisory Council agreed to examine ‘the military opportunities and threats arising from the field’ (my emphasis) (Parliamentary Office of Science and Technology, 2008). Given the grant from the Alfred P. Sloan (a not uncontroversial figure himself) Foundation of $570,060 to ‘explore the risks and benefits of this emerging technology, as well as possible safeguards to prevent abuse, including bioterrorism’ was to be investigated by a collective effort of M.I.T., the J. Craig Venter Institute and the Center for Strategic and International Studies. (MIT News, 2005). So a critical and objective review and account was to be created by the co-founder of MIT’s Synthetic Biology Working Group (and a large part of the iGEM competition), a leading research centre that has already spent years and raised millions from venture capital to exploit the new technology and the Homeland Security section of the CSIS. Given these examples, coupled with the promoted “closer working relationships” between intelligence services and the biological sciences mentioned above and the evidence of woefully low levels of awareness of key policy concerning biosecurity amongst synthetic biologist researchers would make even recognition of potential military use/misuse of research an unlikely event to be reported. (Kelle, 2007). These things would seem to suggest that the threat of Bioterrorism rests more with those who have put sustained political and financial backing into a range of military applications and increased deregulation of the industry than with malcontents and students.

Artificial Life and Genetic Reductionism

The drive for the minimal genome has raised questions about a working definition of ‘life’, whether this will differ from what we regard as ‘human life’ and the threat of a definition of life working solely in terms of DNA. The most common phrase thrown around this area is the accusation of ‘playing God’. The definition of ‘life’ is key to much of the confusion and uncertainty in this area of study. Although it is often said a large part of the objection from this kind of work comes from religious sensibilities, there is no real definition of life amongst the major religions of the world, indeed they often rely on the same scientific definitions such as ‘metabolic properties, the ability to respond to the environment or replication.’ (Cho et al, 1999). Indeed the search for a ‘minimal genome’ could be misleading as there may be multiple minimal genomes ‘depending on what the organism is expected to do and under what environmental circumstances the organism is placed.’ (Cho et al, 1999). It is not only religion which is struggling with an acceptable definition and understanding of what constitutes life. Aristotle’s scala naturae, which would later become the ‘Great Chain of Being’ in Christian theology, was more descriptive than explanatory, although Aristotle at least went into some effort to describe the different nature of souls present on different tiers of the scale. There was no serious attempt to do more than classify and scale in formal epistemology. In discussing the history of knowledge Foucault said ‘At the end of the eighteenth century, the description and analysis of these natural beings showed, through the use of more highly perfected instruments and the latest techniques, an entire domain of objects, an entire field of relations and processes which have enabled us to define the specificity of biology in the knowledge of nature. Can one say that research into life has finally constituted itself in biological science? Has the concept of life been responsible for the organisation of biological knowledge? I don’t think so. It seems to me more likely that the transformations of biological knowledge at the end of the eighteenth century were demonstrated on one hand by a whole series of new concepts for use in scientific discourse and on the other hand gave rise to a notion like that of life which has enabled us to designate, to delimit, and to situate a certain type of scientific discourse, among other things. I would say that the notion of life is not a scientific concept; it has been an epistemological indicator of which the classifying, delimiting, and other functions had an effect on scientific discussions, and not on what they were talking about.’ (Foucault, 1971) Of course that was 1971, when even recombinant DNA technology was a new idea. Perhaps the concept of life wasn’t the reason for early biological epistemology, but could the work of synthetic biology, in the area of the minimal genome and artificial life actually play a role in changing the use of the word life from an epistemological indicator to a scientific concept in its own right? After all much of this field is actually driven by a desire to understand the functions, limitations and threshold of life. A leader in this area is of course Dr Venter; ‘What is life? I don't think there are that many biologists trying to answer that one.... We're...working on a reductionist view of trying to take the smallest genome that we have...and see if we can't understand how those...[genes] work together to create life...’ (Cho et al, 1999). Such a reductionist approach is questioned by Cho et al, who mention how reductionist logic has led to erroneous conclusions such as thinking that viruses were the phylogenetic precursors to cellular life. Where does the ethics of synthetic biology apply to all this? Is this not simply academic wrangling over a conceptual definition? This cannot seriously be conceived as the case. There is concern that making such debate an ethical matter may lead to a fracturing of opinion based on different ethical foundations between different religions, groups and societies. However it is pointed out ‘There are virtually no major ethical differences between the basic texts of Judaism, Christianity, Islam Buddhism, Confucianism and Greek and Roman applied philosophy. The four Confucian qualities are goodness, conscience, reverence and knowledge. You may debate these, but they reflect the same concepts, and, when carefully translated, the same words as the various European traditions.’ (Saul, 2001) In fact those four traits can be seen to be mirrored in many secular societies as well, arguing for goodness, conscience, knowledge and for example in environmental groups, a reverence towards our ecosystems. Saul argues that there are very few issues on which there can be no consensus, ‘What about the daily questions we must deal with? How many are ethically unresolvable within the Western tradition? Very few. Of course, there is endless room for disagreement and debate, but not to a degree which must fracture societies.’ Furthermore, ‘That there are periodic unresolvable issues does not mean that ethics doesn’t work.’ These points are instructive to all of us concerning synthetic biology. The idea that there are not countless, all mutually incompatible positions throughout the majority of ethical frameworks give us less reason to exclude these from the thought process on developing the research. Even on particulars where some remain irreconcilable, this cannot be interpreted as an ethical failure or warrant a marginalisation of ethics in the field. Debate and discussion are an intrinsic part of scientific history and development and indeed reason itself can be understood as thought and argument, so these should if anything be encouraged within synthetic biology. Cho et al argue for a need for ‘scientific and public policy communities [to] stop placing religion and science in opposite camps when it comes to advances in science’ (Cho et al, 1999). Particularly in synthetic biology with so many potential empowering and beneficial possibilities, many religious individuals and institutions are far from hostile towards it. ‘the dominant view is that while there are reasons for caution, there is nothing in the research agenda for creating a minimal genome that is automatically prohibited by legitimate religious considerations. Moving forward with caution requires that the scientific communities be in continual conversation with the entire society, working together to address key ethical and religious concerns.’ (Cho et al, 1999). In thinking about definitions of life, it should be recalled it was in fact scientific thinking that played a role in putting humanity back as a part of the rest of life on the planet through understanding of our evolution and such an almost ‘animist’ (Saul, 2001) tradition has played a role in many scientific arguments for seeing life as interconnected and more than just organized matter (Cho et al, 1999). The discussion and debate here will surely centre on the absence of a fixed definition to answer what ‘life’ is. Edward Machery, a philosopher of science at University of Pittsburgh has gone as saying the idea of a stable definition would be ‘impossible and useless’ (Balmer, 2008), that synthetic biologists are confused over what life is and how complex it must be. Similarly an editorial in Nature in 2007 argued ‘It would be a service to more than synthetic biology if we might now be permitted to dismiss the idea that life is a precise scientific concept’ (Balmer, 2008). Perhaps the crux of the matter lies in accepting uncertainty in the definition of life. ‘If Machery is right, that the idea of life is highly complex, but can possibly be defined by science, it would require multiple definitions across multiple fields. What implications might this have for an ethics that sought to trouble synthetic biology at the level of life definition? Put another way, if life is not a stable concept how might one argue that it is fundamentally immoral to create it?’ (my emphasis) (Balmer, 2008). To accept a degree of uncertainty may cause problems for a number of people but certainly it should not for scientists, the comment that ‘Often all it takes is a literary allusion to the idea that truth exists only in the plural – that there is no such thing as a single truth but only a multitude of truths – to make the defenders of one or another truth sense danger, mortal danger.’ (Grass, 1999) should not prove difficult to accept given the consistently questioning nature of scientific endeavour, applied doubt and the search for understanding and facts rather than perfect, absolute truths. Ethics too possesses this questioning nature, rather than a crystallized absolute decided upon and never to be reconsidered. We are all ‘perfectly capable of asking ourselves the ethical questions. Once asked they demand not so much replies as continual, sustained questioning. To ask is to admit that we have both a need and an obligation to ask, to go on asking and, along the way, to act in accordance. To ask and not go on is to admit personal failure as an ethical being’ (Saul, 2001)

Patents, Trade and Justice

Rousseau commented “Liberty without justice is a veritable contradiction”. This sentiment may explain why perhaps one of the most fractious areas of debate concerning synthetic biology has been in terms of patents, trade and justice. It is of course not surprising that the potential to create microorganisms which can produce fuel such as ethanol or medical components such as artemisinin has attracted such a level of interest and investment. The potentials are indeed great, but many questions concerning the nature of investment and subsequent patenting of innovations have occurred. Dr Venter’s work on producing hydrogen for fuel from a synthetic form of Clostridium has received a large level of funding, including an expected $125m over the next five years from US Department of Energy. Additionally, the DoE is investing $385m in six commercial scale cellulosic ethanol biorefineries, working alongside private companies including Cargill, Dow, DuPont, Shell, Iogen. Universities play a large part of course in this area, such as the $500m ‘alliance’ between BP and UC Berkeley. (ETC Group, 2008) and subsequently ‘As huge amounts of money are being invested in synthetic biology groups it is clear that there are high expectations of a significant commercial return.’ (Balmer, 2008). Indeed the potential of the market is certainly deemed to be lucrative, ‘Bio-Economic Research Associates (Cambridge, MA) predicts that bio-based chemical processes could capture more than $70 billion in revenues by 2010 – more than 10% of the global chemical industry total. (One analyst predicts that the market for bio-plastics will expand from $1 billion in 2007 to over $10 billion by 2020.6) The biofuels sector could reach $40 billion by 2010 and $110-150 billion by 2020. Revenues from vaccines developed with next gen¬eration DNA technologies could reach $20 billion by 2010’ (ETC Group, 2008). This has led to accusations of some major players trying to form an early monopoly of the field through wide ranging patents. (ETC Group, 2007) Such claims are perhaps exacerbated by comments such as Dr Venter claiming in The Sunday Times in 2007, ‘Obviously, if we made an organism that produced fuel, that could be the first billion or trillion-dollar organism’ (Balmer, 2008). In this context, Dr Venter’s patent applications on minimal living cells or on the making of synthetic genomes (UPSTO no. 20070264688) (Balmer, 2008) appear to be little more than an updated version of an overly broad patent forming a cartel, such as that by George Baldwin Selden and his patent granted in 1895 for a four-wheeled self-propelled vehicle. Perhaps luckily for the automotive industry, Henry Ford managed to overturn the patent in an appeal to an already lost case, in 1911. Such a comparison to the current situation is made even more fitting by the common use of the term ‘chassis’ to describe the minimal genome. The origin of much of the current issues facing biotechnology as a whole is the outcome of the Diamond v. Chakrabarty case, where the U.S. Supreme Court ruled in a 5-4 verdict “A live, human-made micro-organism is patentable subject matter under 101. Respondent's micro-organism constitutes a "manufacture" or "composition of matter" within that statute’ (U.S. Supreme Court, 1980) This allows for patenting of genetically altered organisms as they were deemed to be not products of nature. There is left some ambiguity over the patenting of individual genes and use in research and newly assembled genomes. ‘Current patenting practises may already be restricting development of and access to clinical applications of genomics, as well as academic and industry researchers’ access to genetic information and reagents. Large-scale gene identification efforts such as that involved in minimal genome research, as well as other technologies that require use of large numbers of genes simultaneously (such as gene arrays have great potential to exacerbate these problems.’ (Cho et al, 1999). They go on to suggest that new legislation will have to be passed, explicit to genes and organisms to help protect everyone’s interests. The problems with Intellectual Property Rights are by no means restricted to synthetic biology, an example is of criticism of their role in the production (or lack thereof) of generic drugs for HIV treatment. Where synthetic biology is distinct is that its part in intellectual property is ‘at the confluence of biotechnology and computing’ (Rai and Boyle, 2007). They point out the problems that the development of computer software caused in fitting the remit of neither patents nor copyrights in intellectual property terms was ‘hardly resolved by forcing it under both. Rai and Boyle suggest the difficulty with the way in which the law handles software and biotechnology individually could come together to form ‘a perfect storm’’ (Balmer, 2008). There are critics of synthetic biology in this area such as the already mentioned Action Group on Erosion, Technology and Concentration (ETC) who have been particularly critical of one of the early “success stories” of the field, namely the development of artemisinin for anti-malarial drugs. This work, being conducted by OneWorld, UC Berkeley and Amyris, has been largely funded by donations of $42.6m from the Bill and Melinda Gates Foundation. They argue it has ‘become the raison d’être of synthetic biology and given the field a philanthropic sheen’. They suggested that its results have been greatly inflated to keep up funding, which simultaneously undercuts funding going to what they argue are more effective programs and ruining farmers in the third world who rely on growing wormwood for artemisinin, thus concentrating the supply and power ever more in the hands of multinational corporations. (ETC Group, 2007). Furthermore when the World Health Organisation (WHO) recommended artemisinin should be integrated with other anti-malarial drugs in ‘Artemisinin Combination Therapies (ACTs), to ensure that resistance does not build up’(Balmer, 2008) which seems a reasonable action, but as they continue, ‘However, ETC argues that Novartis has a virtual monopoly on ACTs and quote the Royal Tropical Institute of the Netherlands ‘This monopoly-like situation has created an imperfect market defined by scarcity of raw materials, speculation and extremely high retail prices’’. However, polemically, ETC didn’t acknowledge (to the best of my knowledge), the role Novartis at least has played in providing qinghao (wormwood) to developing countries free or at cost (Stiglitz, 2006). It could also be countered that the production of artemisinin through synthetic biology would help lower the cost, however this is uncertain, but what is certain would be the ruination of wormwood production in developing nations and inability for local, competitive production of anti-malarial products which will only reinforce monopolies and the ensuing discrepancy of wealth and health. This sentiment is echoed across a range of reviews ‘there are other ways of reducing malaria mortality that would not make people in developing countries dependent on companies in rich countries’ (IDEA League, 2007). It may be sensible to recall as Milton Friedman said “Concentrated power is not rendered harmless by the good intentions of those who create it.” The ethics of all this? It is currently popular to describe and aspire towards “sustainable development”, a decidedly vague term at best (Ferry, 2007). However this takes as an assumption that economic expansion, labelled development is always our objective. This has been regardless of the effects of mass urbanization and industrial agriculture throughout much of the developing world. You cannot seriously argue that business and a degree of self-interest are inherently bad of course, but neither can they be expected to lead an ethical society. After all, there is no inherent relationship between logic or rationality and ethics. There is certainly not an inherent link between self-interest and ethics, nor technological advances and ethics. For example take IBM Hollerith punch-card machines, ‘Throughout the 1930s it helped us streamline our aging nineteenth-century administrative methodologies. It helped us organize policies for a greater number of citizens and could be seen as a handmaiden of egalitarianism. It was also used throughout the Nazi regime to streamline the identification, listing and deportation of Jews. At Auschwitz, prisoners kept for labour had their forearms tattooed with five-digit, IBM Hollerith-machine identification numbers.’ (Saul, 2001). On the other hand, it is often noted that more egalitarian societies show lower levels or costs of crime, obesity, health care etc, examples include (Nord et al, 1995) (Richardson, 2001), (Islam et al, 2006) and (Kagamimori, 2009). Indeed it is common that ethical principles will be aligned with those of self-interest, that the cost now will be worth it in the end. But that must not be confused with being the nature of ethics. ‘But if you believe that ethics pays, what are you to do if it doesn’t? Marginalize it? Abandon it? Fall back on charity and pity?’ (Saul, 2001). On closer analysis, the concept that ethics pays cannot truly be deemed an ethical one. A great deal of the ethical arguments come from non-governmental organisations (NGO) such as ETC, some of whose work I have utilised. However, as interesting and perhaps admirable as the recent flourishing of NGOs and the many young people engaged in them might be, they cannot be held free from criticism themselves. Aside from the obvious criticisms of the crass and the stupid, for example pro-life groups in the US murdering doctors, there is a perhaps a more general criticism to be made in terms of the ethical implications faced in biotechnology and many other areas of controversy. A sample of articles containing criticism of biotech initatives and of the critics are in the references below under the heading ‘Criticism and Critics’ to illustrate this idea, some of the criticism and if you read the comments, some of the hysteria that surrounds the issues. Any critical review of a large number of NGOs, many of which are truly single issue organisations, cannot escape from noting an ‘underdog’ complex, an arguably self-righteous and smug attitude, for example the Colalition Against Biopiracy award ceremony named the ‘Captain Hook Awards’ where they lambast those they deem “Biopirates” and laud those they call “Cogs” (after the merchant ships which featured a design to protect them from piracy) for fighting against the “pirates”. (Convention on Biological Diversity, 2008). As no doubt humorous and well intended as the sentiments are, it is hard to defend such a polemic, self-aggrandizing (through the role of the underdog), self congratulatory antics as worthy of individuals who can be considered willing to give serious, impartial debate to such an issue. Compounding these tendencies is that many NGOs who lead the debate on ethics in such areas spurn legitimate, democratic representation; personal, self-justified actions are undertaken without generalized debate or discourse. An example would be the actions of People for the Ethical Treatment of Animals (PETA) or those of the Stop Huntingdon Animal Cruelty (SHAC) groups. Leaving aside whether their complaints have been valid, what could be argued as ethically questionable about these and other NGOs is that ‘the people who have set and who continue to set the ethical agenda of our time are absent from the chambers to which the citizens send their representatives. They don’t want to be there. When pressed, they tend to respond that elected officials have no real power. But if they don’t believe it is worth being elected, then they don’t believe in democracy. If they don’t believe in democracy, what do they think should replace it? And however much they believe they are right, do they not believe that the citizenry have the right to make the final decision? If so, how, since they themselves have rejected the legitimacy of the legislature? If not, then how do they differentiate themselves from others who believe that it is they who are right, also reject democracy, and happen to disagree with the NGO in question? The growing neo-fascist movements, for example.’ (Saul, 2001). He elaborates this point by saying ‘The levers of power are inside. If you’re not there – elected and present – your only hope is to influence those who are. Suddenly your role is not that of a public person, but of a courtier – a lobbyist. You are on the outside, lobbying for change. Even if the cause is good, a lobbyist is a lobbyist is a lobbyist.’ This is not to argue we should only protest ‘via the ballot box’ after all it could be argued the lack of legitimate representation by their politicians has driven many to form and work for these NGOs. This necessary point raised, it must be noted that when it comes to synthetic biology, trade and justice, facts such as ‘Not only are industrial agrofuels driving the world’s poorest farmers off their land and into deeper poverty, they are the single greatest factor contributing to soaring food prices’ (Mitchell, 2008)(in a leaked report from the World Bank) and a large degree of the research and work being conducted in synthetic biology is by companies such as BP, GM, DuPont, Pfizer, Cargill, Dow Chemical, International Paper, Microsoft, Royal Dutch Shell, Chevron, ExxonMobil etc (ETC Group, 2008). These companies represent the largest or some of the largest corporations in their fields, which when coupled with many having a less than unassailable ethical record perhaps validate concerns that there is no reason to expect that synthetic biology will be any different than many other areas in terms of balancing the rights of all stakeholders. To return to the nature of patents and intellectual property regarding synthetic biology, there are many past examples that we should use to anticipate likely developments and hopefully improve on past mistakes. The company Myriad Genetics could be said to embody some of the fears concerning intellectual property and genetics. It patented mutations in the BRCA1 and BRCA2 gene, the presence of these mutations show increased susceptibility to breast and ovarian cancers. The company ‘has demanded that even not-for-profit labs screening for mutations pay a license fee, thus discouraging screening.’ (Stiglitz, 2006) Dr Skolnick of Myriad argued in favour of such patents saying ‘If it’s not patented you won’t get some group to spend money to develop it, and you won’t get a high-quality, inexpensive test’ (Rimmer, 2008). Aside from pointing out the work of world renowned institutes like the Sanger Institute or Medical Research Council in the UK, or the National Institutes for Health in the US, who in fact did a large proportion of the work on BRCA1 with Myriad, raising the issue of genetic work and to whom gets the patent when so much work is collaborative and developed on top of earlier research, ‘If every time a researcher had an idea, he ran down to the patent office, he would spend more time there – or with his lawyers – than in the lab’ (Stiglitz, 2006), aside from those institutions or the state funded Human Genome Project (HGP) which led to its own patent problems when private enterprises tried to patent genes, 7,500 applications from Human Genome Sciences, 6,500 from Dr Venter’s Celera Genomics and a staggering 36,000 applications from a French firm Genset, all no doubt necessary spurs to invention despite the fact the HGP had already decoded the entire genome. Aside from these doubts that could be cast on such claims from Myriad, the renowned research centre, the Institut Curie also called such commercial testing a barrier to patient care, noting ‘the initial family mutation searches performed by Myriad are billed at 2400 United States dollars (18000 francs – 2744 Euros), as against an estimated cost of 5000 francs (762 Euros) for testing in French laboratories’ (Rimmer, 2008). The Institut filed an opposition to Myriads patent on BRCA1 on grounds of lack of novelty, lack of inventive step and insufficient description. They successfully challenged the patent, which was rescinded. However the patent would then be subsequently upheld in a case for University of Utah Research Foundation (to whom Myriad relinquished patent ownership to), an interesting note on this case is from the response from the European Patent Office to the Opposition’s argument that the patent offends public morality and human rights, ‘None of the objections of the [Opposition] demonstrated that the publication and exploitation of the invention in suit is contrary to the ‘ordre public’ or morality. The objections were aiming at the negative effects of the patenting itself of the invention, at the financial and economic drawbacks and at the dependencies and negative consequences for the national health systems.’ (Rimmer, 2008), Rimmer observes ‘The reasoning here is somewhat odd - the Opposition Division dismisses the ethical and human rights objections of the opponents by characterizing them as merely economic arguments. The decision highlights how the European Patent Office narrowly construes exclusions from patentable subject matter on the basis of ‘ordre public or morality’’ The problems of Trade-Related Aspects of Intellectual Property Rights (TRIPs) are of course not a factor solely for synthetic biology. However, given the role these have played in related fields of biotechnology and pharmaceuticals, synthetic biologists must start to take action now to avoid a repetition of past injustices. Patents are supposed to encourage innovation, but once again, extreme positions have clouded a fair debate. Few are arguing for a complete abolition of property rights and copyrights of any kind, but ‘TRIPs was designed to ensure higher-priced medicines. Unfortunately, those prices made medicines unaffordable to all but the wealthiest individuals. As they signed TRIPs, the trade ministers were so pleased they finally reached an agreement that they didn’t notice they were signing a death warrant for thousands of people’ (Stiglitz, 2006). And that is ultimately what it comes down to, the deaths of thousands across the developing world, for lack of drugs despite the fact that for drug companies for instance ‘African sales represent under 2 percent of the total’ (Stiglitz, 2006). ‘The instrumental position is that the human right of a corporation to protect its intellectual property trumps the medical need of a sick person’ (Saul, 2001). Saul rejects as “pseudo-rational” the intellectual property arguments saying ‘The terminology used is terrifyingly clear about how reason is thought of. It is to be essentially utilitarian. Thought – of which the intellect is an element – is merely property.’ He furthermore highlights problems of ‘a civilization to attempt to live off licensed knowledge is the intellectual re-creation of the old absentee landlord problem.’ Stiglitz doesn’t even give it that much credit, ‘If you own a piece of land, you can do with it as you please, so long as you remain within the law: obeying zoning requirements, not establishing a brothel, or – most important for our purposes – not conspiring with others who own similar properties to create a monopoly that, left unchecked, may lower economic efficiency and threaten public welfare. …By contrast, intellectual property rights actually create a monopoly. The monopoly power generates monopoly rents (excess profits), and it is these profits that are supposed to provide the incentive for engaging in research. The inefficiencies associated with monopoly power in the use of knowledge are particularly serious, because knowledge is what economists call a “public good”: everybody potentially can benefit from it; there is no cost of usage.” (Stiglitz, 2006) Stiglitz writes in terms of a solution concerning the particular medicinal problem, but given the artemisinin research that plays so much a part in perception of synthetic biology, this problem is of vital importance to synthetic biology to assert its position in global trade, justice and public perception and far more importantly potentially vital for many in the worlds poorest nations. He recommends a more nuanced set of intellectual property rules rather than simply enforcing Euro-American regimes (which he argues are even counter-intuitive to their own national interests) but also suggests ‘One of the simplest ways for the developed countries to help developing countries is to “waive” the tax, allowing them to use the intellectual property for their own citizens, so that their citizens can obtain the drugs at cost. Critics might say: But then the developing countries are simply free-riding on the advanced industrial countries. To which the answer is: Yes, and they should. There is no additional cost imposed on the developed countries. And the benefits to the developing countries would be enormous: increased health is not only of value in its own right, but it would contribute to increased productivity.’ He follows this with perhaps the key point for this particular review, ‘A start in this direction has already been made. Students at some research universities are arguing that the universities should insist that, as a part of their licensing agreements with drug manufacturers, drugs be provided to developing countries at deeply discounted prices.’ (Stiglitz, 2006) Surely iGEM, as an undergraduate international collaboration, featuring universities from many different nations is a perfect forum for the ethical agenda of synthetic biology to take part, a role already started, though by no means complete or assured, with the Creative Commons nature of the BioBricks registry. There is a great tradition of the free flow of information throughout academia and of collaborative, open work throughout such institutions, the Human Genome Project being a great example of the potential that arises from an amalgamation of pure, scientific inquiry fostered in a socially considerate context. If we are serious about ethics in synthetic biology and it isn’t just a cheap PR move, then the responsibility rests with us to work towards making such policies integral to the area now, through debate, open collaboration and partnerships with civil society groups, social scientists and all community stakeholders, an understanding and drive to form an appropriate framework of legislation for regulation and economic purposes. And in that context, there can be a little better forum to shape such initiatives than that of iGEM and the students who may be the first generation of graduates to define themselves as “synthetic biologists”.

Finally, perhaps it may be of use to all parties, research groups, state departments, private enterprise and NGOs to recall the words of Adam Smith, the much quoted thinker held in part responsible for the development of our current economic model, ‘[H]e is certainly not a good citizen who does not wish to promote, by every means in his power, the welfare of the whole society of his fellow-citizens.’(Smith, 1759) A citizen, so part of a society, must use “every means”, not selective whenever it is felt like, to promote the welfare of the entire society and “fellow-citizens” equal members one and all, not separate or inferior than those from the company, government or society one is a part of. Hardly a simple thing to try to do, but ethical action has never really been considered easy, even though it may hopefully become considered normal.

References and Further Reading

Balmer, A. & Martin, P. (2008), Synthetic Biology – Social and Ethical Challenges http://www.bbsrc.ac.uk/organisation/policies/reviews/scientific_areas/0806_synthetic_biology.pdf

Bhutkar, Arjun, (2005) “Synthetic Biology: Navigating the Challenges Ahead” Journal of Biolaw and Business, Vol 8(2) pp. 19-29 http://www.genomics.arizona.edu/PDFs/Bhutkar%202005%20Synthetic%20biology.pdf

CAE Defense Fund, for details on this case and its relevance to “bioterrorism” see http://www.caedefensefund.org/overview.html#kurtz

Cho, Mildred K., Magnus, David, Caplin, Arthur L., McGee, Daniel, and the Ethics of Genomics Group, (Dec 1999), “Ethical Considerations in Synthesizing a Minimal Genome”, Science, Vol. 286, no 5447, pp. 2087-2090 http://www.sciencemag.org/cgi/content/full/286/5447/2087#ref10

Convention on Biological Diversity, (2008) “Captain Hook Awards for Biopiracy 2008” http://www.etcgroup.org/en/materials/publications.html?pub_id=690

Criticisms and Critics http://www.mindfully.org/GE/2004/Bayer-Bashing-Britain2004.htm http://www.biotech-info.net/GE_critics.html http://www.commondreams.org/archive/2008/01/23/6563

de Jonge, Boudewijn, ( Jan, 2006) “A Socio-Legal Analysis of the Failed Establishment of the Organisation for the Prohibition of Biological Weapons” University of Amsterdam, Institutional governance and reform (can be found online at http://www.scribd.com/doc/9228514/Organisation-for-the-Prohibition-of-Biological-Weapons )

ETC Group, (Jan, 2007) “Extreme Genetic Engineering: An Introduction to Synthetic Biology” http://www.etcgroup.org/en/materials/publications.html?pub_id=602

ETC Group, (Nov, 2008) “Who Owns Nature? Corporate Power and the Final Frontier in the Commodification of Life” http://www.etcgroup.org/en/materials/publications.html?pub_id=707

Ferry, Luc, (Oct-Nov, 2007) “Protéger l'espèce humaine contre elle-même” Revue des Dux Mondes, pp. 75-79

Flachowsky G., Halle I. and Aulrich K., (Dec, 2005) “Long term feeding of Bt-corn – a ten generation study with quails” Archives of Animal Nutrition, Vol. 59(6), pp. 449-51

Foucault, Michel, (1971), “The Chomsky – Foucault debate on human nature” The New Press, New York, 2006

Grass, Günter, (Dec 1999) “To Be Continued…” Nobel Lecture. http://nobelprize.org/nobel_prizes/literature/laureates/1999/lecture-e.html

IDEA League Summerschool, (Aug, 2007) “Synthetics: the ethics of Synthetic Biology” IDEA League Summer-school, The Netherlands, http://www.ethicsandtechnology.eu/images/uploads/Ethics_of_synthetic_biology.pdf

Islam, M Kamrul, Merlo, Juan, Kawachi, Ichiro, Lindstrom, Martin and Gerdtham, Ulf G., (Apr, 2006) ”Social capital and health: Does egalitarianism matter? A literature review” International Journal of Equity Health, Vol. 5:3 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1524772

Josefson, Deborah, (Jul, 2002), “Scientists Manage to Manufacture Polio Virus” British Medical Journal, Vol. 325(7356): 122 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1143801

Kagamimori, S., Gaina, A., Nasermoaddeli, A., (Jun 2009) ”Socioeconomic status and health in the Japanese population” Social Science & Medicine, Vol. 68(12) pp. 2152-60

Kelle, Alexander, (Nov, 2007) “Synthetic Biology & Biosecurity Awareness in Europe” Bradford Science and Technology Report No. 9 http://www.idialog.eu/uploads/file/Synbiosafe-Biosecurity_awareness_in_Europe_Kelle.pdf

Losey, John E., Rayor, Linda S. & Carter, Maureen E., (May, 1999) “Transgenic pollen harms monarch larvae” Nature 399, p.214 http://www.nature.com/nature/journal/v399/n6733/full/399214a0.html

MIT News, (Jun, 2005) “Study to explore risks, benefits of synthetic genomics” http://web.mit.edu/newsoffice/2005/syntheticbio.html

Mitchell, Donald, (Apr, 2008) “A Note on Rising Food Prices” World Bank, draft document http://image.guardian.co.uk/sys-files/Environment/documents/2008/07/10/Biofuels.PDF

Nord, Erik, Richardson, Jeff, Street, Andrew, Kuhse, Helga and Singer, Peter, “Maximising Health Benefits Versus Egalitarianism: An Australian Survey of Health Issues” Centre for Health Program Evaluation, Working Paper 45 http://www.buseco.monash.edu.au/centres/che/pubs/wp45.pdf

Parliamentary Office of Science and Technology, (Jan, 2008) “Synthetic Biology” Postnote, No.298 http://www.parliament.uk/documents/upload/postpn298.pdf

Rai, Arti and Boyle, James, (Mar, 2007), “Synthetic Biology: Caught between Property Rights, the Public Domain and the Commons” PLoS Biology 5(3):e58 http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0050058

Richardson, Jeff, (Oct, 2001) “Why Economic Costs May Not Be Of Interest In A National Health Scheme; Or, Costs Fairness And Reverse Order Analysis” Centre for Health Program Evaluation, Working Paper 126 http://www.buseco.monash.edu.au/centres/che/pubs/wp126.pdf

Rimmer, Matthew, (2008), “Intellectual Property and Biotechnology” Edward Elgar Publishing, Cheltenham, 2008 [http://books.google.co.nz/books?id=gZqGPaMnS1QC&pg=PA187&dq=Myriad+Genetics&sig=ACfU3U0S_MgEhZ-jOEaf1cQJnO8AS_YkbQ#v=onepage&q=Myriad%20Genetics&f=false Google Books]

Saul, John Ralston, (2001) “On Equilibrium” Penguin Books Canada, Ontario, 2001

Smith, Adam (1759) “The Theory of Moral Sentiments” Text can be found at http://www.adamsmith.org/smith/tms/tms-p6-s3-c2.htm

Stiglitz, Joseph, (2006), “Making Globalization Work” Penguin Books, London, 2007

Szybalski, W. (1974) In Vivo and in Vitro Initiation of Transcription

Tucker, Jonathon B. and Zilinskas, Raymond A., (2006) “The Promise and Perils of Synthetic Biology” The New Atlantis, Vol. 12 (Spring 2006), pp. 25-45 http://www.thenewatlantis.com/docLib/TNA12-TuckerZilinskas.pdf

U.N., (Nov, 2001) “Proposals – Working paper by the United Sates of America” Fifth Review Conference of the States Parties to the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on their Destruction. BWC/CONF.V/COW/WP.17 http://www.opbw.org/rev_cons/5rc/docs/rev_con_docs/cow/COW-WP.17.pdf

U.S. Supreme Court, (Jun, 1980) “DIAMOND v. CHAKRABARTY, 447 U.S. 303 (1980)” http://caselaw.lp.findlaw.com/scripts/getcase.pl?court=us&vol=447&invol=303

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