Team:KU Leuven/Human Practices/Ethics/Normative

Aside from the descriptive evaluation of synthetic biology in general and our project in particular that can be found here, we also made a normative evaluation. A descriptive evaluation differs from a normative evaluations. Whereas man describes ethical beliefs of different persons in a descriptive evaluation, in a normative evaluation how one ought to act is the main topic. We will evaluate our project against the background of the literature on ethics and synthetic biology. This evaluation will include the three typical topics: biosafety, biosecurity and justice.

Human Practices

It is our sincerest hope that this evaluation finds an interested public. Input from this public can only increase the richness of our work.

Human practices encompasses a broad array of subjects, it involves social, legal and ethical aspects. In regard to synthetic biology it emphasises on the economic, political and cultural forces that may influence the development of this young science and the possible impact on human security, health and welfare.
Because of this broad reach there are many players who have a say on the subject. Social scientists, security analysts, bioethicists, engineers and biological science studies practitioners all play their respective roles.
Inspired by this diversity we continuously searched for extensive feedback from all possible angles. Even within one topic such as ethics many different approaches exist. One of these is the normative evaluation. An normative evaluation attempts to examine standards for the rightness and wrongness of conduct and mainly deals with the question how one ought act. This process is important when considering for example a future release of modified organisms in the environment. Since we desire to design more than a mere hypothetical solution it is only logical to pursue such an evaluation, even if we will not produce our bacterium on large scale within the iGEM competition.
We hope to give you, the reader, a glimpse of the existing ethical framework surrounding synthetic biology. Therefore, we searched the current literature for relevant articles on ethics and synthetic biology. It is our sincerest hope that this evaluation finds an interested public. Input from this public can only increase the richness of our work. Democratic deliberation is one of the cornerstones of the ethical framework upon which regulations surrounding synthetic biology should be based (Gutmann, 2011).

An ethical description

“The quality of our lives is determined by the quality of our thinking. The quality of our thinking, in turn is determined by the quality of our questions.” (Elder and Richard, 2006). And ethics after all revolves around asking the right questions.

The acceptance of synthetic biology, for the layman, is driven mainly by media and public perception. Therefore many iGEM teams have done their utmost to reach out to this public. An informed public can participate in the debate and in the subsequent hopefully broadly carried, democratic and well informed decision making process. This broad input does not in any way lessen the responsibility of the scientists in the lab. Some state that “Scientists are not morally responsible for how their work is used” (Douglas T. and Savalescu J., 2010). However, in order for society to trust the scientific community, scientists and engineers need to show that they take risks seriously and consider the implications of the research being pursued.
This is why an ethical description of each project is and will remain a necessity. Not only to show the layman that we do not blindly perform experiments “because we can” but as an instrument to reflect on our own practice and projects. To identify and mitigate risks, to correctly evaluate benefits and to come to a deeper understanding of what it is that you are doing. Or as Linda Elder puts it so eloquently: “the quality of our lives is determined by the quality of our thinking. The quality of our thinking, in turn is determined by the quality of our questions.” (Elder L. and Richard P., 2006) And ethics after all revolves around asking the right questions. We write this text to aid us in asking the right questions and to help guide the development of our project in a just way.

The Framework

The question of where it ultimately comes down to this is: “When is knowingly imposing a risk morally justifiable?” (Calladine & Ter Meulen, 2010).

A new approach to an existing problem has merit when its benefits outweigh its disadvantages and if the new model has a more favourable benefit/disadvantage ratio than the currently existing strategies. Not only this, but it also has to fall between the boundaries of what we consider just and ethically acceptable, even if it is more effective. The key question in this paragraph is: “When is knowingly imposing a risk morally justifiable?” (Calladine & Ter Meulen, 2010).To define these benefits and risks, we will adopt two widely accepted views. The first is the Eco-centric view, which states that not only humans but the entire biosphere has an intrinsic moral value. The second view that we consider is an anthropocentric view which defines ‘good’ as beneficial for humanity.

Eco centric view

Some eco-centric ethicists may have fundamental problems concerning the modification of existing life forms. They state that all living organisms have moral standing and thus deserve moral consideration (Deplazes-Zemp & Biller-Andorno, 2012).There are some difficulties with this view: where, for example, do you stop considering something alive? Further there is also Hume’s law: it is not because something is in nature that it also automatically is what ought to be. A detailed overview of these remarks is unfortunately beyond the reach of this text.
Our project aims for a positive impact on the ecological system by the reduction of pesticide use. The organism we modify is a bacterium. Bacteria do not have a nerve system and it is therefore thought that they cannot feel pain. Therefore, most ethicists do not give these organisms equal moral significance compared to for example vertebrates. Indeed, even the sterilisation of objects and therefore the mass eradication of bacteria raises no ethical debate. However, genetically modifying “lower” organisms can be accepted, even by bio-centrists, if its ecological footprint is less than for example heavy duty extraction procedures “Would algae that make gasoline for example, be a more dramatic way of adapting nature to human ends than drilling for oil, processing it and shipping it around the world?”(Kaebnick, 2011).

Anthropocentric view

The anthropocentric view more readily accepts the modification of nature for human use. Nevertheless, even here it is still required to consider our projects’ ecological impact as our well-being is dependent on a careful, sustainable and responsible use of nature’s resources. On the other hand, any risks to humanity weigh very heavily and potential consequences that could endanger the continuing existence of humans would mean that a project should not be pursued.

With these two views we can evaluate the benefits and disadvantages of our project, by addressing the major concerns. This can help us understand the possible risks, but a definite answer to the question at what point knowingly imposing a risk is morally justifiable is not something we alone can give, if at all. The possible risks affect many and all who are potentially affected should have an input in that debate.

“Unexpected interactions between synthetic microorganisms and the environment or other organisms produce risks to the environment and public health. These risks have to be addressed in order to use synthetic biology responsibly. Synthetic microorganisms released into the environment could initiate processes of horizontal gene transfer and affect biotic balances, or evolve beyond their functionality and elicit unprecedented side-effects on the environment and other organisms. Synthetic biology products must therefore address bio-safety issues when they have consequences for ecology and human health.” (EgE, Opinion no. 25., 2009)

The first concern we need to address is Biosafety. “Unexpected interactions between synthetic microorganisms and the environment or other organisms produce risks to the environment and public health. These risks have to be addressed in order to use synthetic biology responsibly. Synthetic microorganisms released into the environment could initiate processes of horizontal gene transfer and affect biotic balances, or evolve beyond their functionality and elicit unprecedented side-effects on the environment and other organisms. Synthetic biology products must therefore address bio-safety issues when they have consequences for ecology and human health.”(EgE, Opinion no. 25., 2009). As mentioned in this definition, we will now highlight the possible environmental impact and the impact on human health. This can be divided in three topics. The risk of exposure in the lab and its consequences, the containment of the bacteria in the lab and the larger environmental impact. The first two are already well regulated by official lab safety measures and protocols.
It is important to understand that it is impossible to eradicate the risk of escape of a modified organism once it enters large scale production and commercialisation, no matter how rigid the safety measures. This is why we will now review the larger environmental impact on both human health and the ecological system more in depth.

Ecological impact

First we consider the impact of the intended use of our product and the possible consequences of incorrect use, by accident or malice. Therefore extensive and long-term ecological impact assessment studies are indeed required before the release of a modified organism can be authorised as is mentioned by the European Group on Ethics in Science and New Technologies to the European Commission, recommendation No. 4: “The group recommends that before an organism, fabricated or modified by synthetic biology, is released into the environment, ecological long term impact assessment studies must be carried out. Data resulting from such studies should then be evaluated taking into account the precautionary principle and the measures foreseen in the EU legislation (Directive on the deliberate release into the environment of genetically modified organisms). In the absence of a favourable assessment the release of organisms fabricated or modified should not be authorised.” (EgE, Opinion no. 25., 2009). These studies are beyond the scope of our project, but it does not release us from the need to consider the possible impact of our project on the environment after intended use or malpractice. It is impossible to foresee every possible effect of each decision, but any responsible human being should at least consider the possible ramifications of their actions. Thanks to our collaboration with interested parties within the industry we can already obtain a first idea of the effectiveness and possible impact of our project on the environment.
To begin with, there is the intended environmental effect of the project: to reduce our dependence on pesticides and their impact on the ecological system. Pesticides can not only be dangerous to human health (eg the unbridled use of DDT in the past, particularly in North America) but also also have an impact the environment and more specificly biodiversity (Oosthoek S., 2012). Biodiversity is essential for the correct functioning of each ecosystem; a decline in biodiversity has a direct impact on our prosperity as well (Cardinale B.J. et al., 2012). Besides these direct systems there are also long term effects caused by degradation products and the accumulation of waste and other harmful side products (Fenner K. et al., 2013).
For more detailed information about the safety of the compounds our bacteria produce see here .
Besides the intended effect of the introduction of our system there are however potential unforeseen and not intended effects. What could be these effects of the spreading of our system into the environment? Is there accumulation of our products in the environment? Will the introduction of beta-farnesene and methylsalicylate affect insects and or other non-target organisms in a harmful way?
A review of the current knowledge surrounding these questions can be found in the above mentioned link. Further answers can only be attained by extensive field trials. Some of these studies have been done, (James, 2005) (Cui et al., 2012) but only focused on the effectiveness of the pheromone on the intended organisms. They did not study the impact on non-target organisms nor long time effects.
Another important element to consider regarding the growth of our bacteria in nature is the fact that current synthetic biology plasmids use antibiotic resistance for positive selection. The spreading of resistance genes is something that has to be prevented whenever possible. We are investigating the possibility of using a toxin antitoxin system to reduce the chances of horizontal gene transfer.
Further safety measures include creating a positive dependence system via an auxotrophic growth system, physical containment and a kill switch.

Human Health

Another key argument in favour of this project is the positive impact on human health caused by a reduction in the use of pesticides. Pesticides are purposefully designed to kill pests and many of these products can also have an effect on humans.
Possible dangers are both acute poisoning and chronic health effects. The long term health effects can arise as a consequence of an acute poisoning and/or can be caused by chronic exposure. Ample data has been acquired over the years indicating a significant effect of pesticides on human health (CAPE). Exposure has been linked to the onset of, among other diseases, lymphomas, disregulation of the immune system and neurological damage, causing for example Parkinson’s disease (Pezzoli G. and Cereda E., 2013) (Burns C. J. et al., 2013).
For these reasons the reduction of our dependency on pesticides is positive for human welfare. Current regulations in the EU require evidence that there is no harm to people’s health before a new compound is approved (European commission).
Of course the possible health risks of our system have to be kept in mind and examined. The specifications of the volatile compounds produced by our system are E-β-farnesene and methyl salicylate. Possible risks of these molecules can be found here.
Further risk assessments will have to be carried out in accordance to EU legislation before an uncontained product release can be considered. Indirect long-term health-related risks associated with the ecological effects of synthetic biology are hard to predict (EgE, Opinion no. 25., 2009). The matter of what a just balance between precaution and action contains will be discussed later on.

Ethical issues arise particularly from dangers of using synthetic lethal and virulent pathogens for terrorist attacks, bio-war, or maleficent uses (‘garage terrorism’, ‘bio-hacking’), particularly if knowledge and skills on how to produce such pathogens are freely available.

The next major ethical topic that we need to address is biosecurity. “Ethical issues arise particularly from dangers of using synthetic lethal and virulent pathogens for terrorist attacks, bio-war, or malicious uses (‘garage terrorism’, ‘bio-hacking’), particularly if knowledge and skills on how to produce such pathogens are freely available. Not only are protocols available online, iGEM actively promotes an open source system where ‘Bricks’ are added to the registry and can be ordered by other teams. Applications of synthetic biology for such purposes include the production of biological weapons, such as new and/or modified pathogenic viruses or bacteria as well as synthetic organisms engineered to produce toxins. The literature on bio-war and the use of bioengineering for bio-defence, bio-offence and terrorism shows the potential of this technology, which may be amplified by synthetic biology” (EgE, Opinion no. 25., 2009).
Biosecurity is a trending topic in recent literature: how to best guide this young science to safekeep the public from harm without stifling the possibilities for new discoveries is a matter of great debate. (Bennet G. al., 2009) (Hayden E. C., 2009) (Kelle A., 2009) (Erickson B., 2011) (Falkow S., 2012)
In a world where ‘bio-hackers’ will be able to perform synthetic biology in their own garage the limits of registering and licensing tools will be tested. Therefore we strongly advocate the necessity for intervention at the educational level. Providing opportunities for open ethical discussions to foster individual and institutional responsibility. This should create a community where not only knowledge can be shared freely but that is capable of self-regulation and is aware of its responsibility to society. This view is inspired by the concept of intellectual freedom and responsibility and regulatory parsimony (the Presidential Commission for the study of Bioethical issues. 2010) (Gutmann A., 2011). Or as the The European Group on Ethics in Science and New Technologies to the European Commission states it: “Ethical issues that arise because of the potential for dual use should be dealt with at the educational level. Fostering individual and institutional responsibility through ethics discussion on synthetic biology is a key issue.” (EgE, Opinion no. 25., 2009). The iGEM competition in which we participate provides an ideal platform for this endeavour since it is a competition for undergraduates.
On the other hand this does not make the need for external regulation superfluous. In our opinion however an active participation of the scientists will lead to a better acceptance of the need for external evaluation. Regulations are best made in dialogue with scientists and using their active participation (Yearley S., 2009). As such, ethics will no longer be about an outsider telling others what they can and cannot do, but instead rooted from within the scientific community.
It however remains true that a single, maliciousperson with access to the right knowledge and equipment still poses a serious threat to the general public. This is extended by the fact that some intended and unintended dual purposes can be foreseen but others not (EgE, Opinion no. 25., 2009).This makes the matter of responsibility so complicated and is the reason why it would be unwise to let just one institution -be it the scientists themselves or one outside regulatory organ- carry the full responsibility. Regulatory oversight is therefore also seen as necessary in the EU and US such as for example a screening infrastructure for genetic sequence providers (EgE, Opinion no. 25., 2009 )( the Presidential Commission for the study of Bioethical issues. 2010).

Dual use dilemma

Mitigating the risk for wrongful use as much as possible is and remains a legislative problem. We are convinced that an effective regulation can be found in dialog with the scientific community and that there is broad willingness to play a constructive role in this debate.

Concerning our project we will limit ourselves to the impact of our project on biosecurity, this leads us to the dual use dilemma. This dilemma arises as a consequence of the fact that one piece of research sometimes has the potential to be used for bad as well as good purposes. A recent example is the H5N1 “affair”. A research group wanted to study which mutations could make the Avian H5N1 flu virus transmittable between mammals. They did this generating the required genome themselves. This led to a passionate dialog about biosafety, biosecurity and bioterrorism which eventually led to a self-imposed moratorium on further research (Falkow S., 2012). The whole is an ethical dilemma since it is about promoting good outcomes in the context of the potential for also causing harm. It is also agovernmental dilemma as these strains van threaten the security and health of their citizens (Miller S., Selgelid S. J., 2007).
The intended consequence of our system is to shift balances in the environment to favour the predation of aphids and to prevent them from thriving in order to increase crop revenue. Dual use would in this case be an effect on non-target organisms or in a non-target environment that is detrimental to the respective ecosystem. The further defining of these dual use situations is yet another reason to perform risk assessments and long term field studies.
It is regrettably so that even with these studies every possible dual use scenario cannot be foreseen. Mitigating the risk for wrongful use as much as possible is and remains a legislative problem. We are convinced that an effective regulation can be found in dialog with the scientific community and that there is broad willingness to play a constructive role in this debate.

Proportionality

Is the release of our project into commercialisation and therefore an inevitable release in the environment justifiable?” Or to put it even more directly: “Are the benefits proportional to the risks?” Our approach might not be the best alternative, but to find out what is, we need to foster research both in the field of synthetic biology and other fields of science. In light of our responsibility to current and future generations.

Justice is the third major ethical topic in synthetic biology and in the end our entire evaluation boils down to this core question: “Is the release of our project into commercialisation and therefore an inevitable release in the environment justifiable?” Or to put it even more directly: “Are the benefits proportional to the risks?” Proportionality is defined by T. Bubela et al. as follows: “Proportionality defines that the response to a new invention should be proportional in balancing risks to health and the environment against the potential benefits of research and novel technologies. It concerns the rightness of the response in balancing the risks and potential benefits and should consider public beneficence; impact on human rights, for example, on health, housing, water and security, responsible stewardship and impact on future generations” (Bubela T. et al., 2012).
The difficulty lies in the fact that the aimed benefits are vast, but the risks largely unknown and hard to quantify. These risks are often referred to as low-probability, potentially high-impact events (the Presidential Commission for the study of Bioethical issues. 2010). However, let us first consider the possible benefits. This project was created with the intention of tackling some of the great international problems we face today, namely food shortage. The eradication of extreme hunger and poverty is millennium goal no. 1 of the UN. Approximately 870 million people in the world do not have enough to eat and hunger kills more people each year than AIDS, malaria and tuberculosis combined (millenniumgoals ) ( >orld Food Program). Moreover, regions with high starvation risks also suffer most from wrongfully applied pesticides with consequences for human health. Our aim, to reduce the consequences of aphid infestations in a durable way is also in line with the global justice discourse. This also affects questions of inter-generational justice, with implications for preserving the environment and natural resources for future generations. (EgE, Opinion no. 25., 2009). We hope to increase crop revenues, decrease the burden on the environment caused by pesticides and thuspreserve biodiversity,as mentioned when we discussed biosafety. Global justice however also requires an equal distribution of both burdens and benefits, for this we refer to the paragraph about distributive justice.
For detailed data on the impact of aphid infestation on agriculture see here.
Only further research will show whether our approach will offer a valid alternative to the current use of pesticides. We understand and respect the current unwillingness of the general public towards GMO’s. However, we believe we also have a responsibility to current and future generations. We therefore strongly advice against a full moratorium on GMO research and on the commercialization of potential results if the only reason would be uncertainty with regards to possible risks. It would deny current and future generation access to all of the possible benefits. We believe that continued research and commercialization is justifiable, providing strong ethical and scientific controls are kept in place.
The European Group on Ethics in Science and New Technologies to the European Commission has opted for a precautionary approach to this new science. However, as stated by the group itself: long-term health-related risks associated with the ecological effects of synthetic biology are hard to predict. (EgE, Opinion no. 25., 2009). What is a justifiable amount of risk? An overly restrictive approach will mitigate research possibilities and never lead to more insight in these long term effects. The precautionary principle does not aim for this scenario but given a strict interpretation (a full moratorium) it could prohibit every action (and inaction) and therefore offer no action guidance at all (Holm S., Harris J., 1999).
Therefore we find ourselves leaning towards prudent vigilance and regulatory parsimony, as stated by The Presidential Commission for the study of Bioethical issues. Here responsible stewardship is balanced with intellectual freedom for continued investigation, establishing only as much oversight as is necessary to ensure public safety and public benefits from the technology (Gutmann A., 2011) (Erickson B. et al., 2011). We are aware that our current data are insufficient to authorize a commercial release, but in the regulatory setting we discussed here, we would have the opportunity to perform the necessary studies to chart potential risks but also benefits.

Distributive justice (and social justice)

All those who will or should benefit and all those who can be adversely affected by our project should have input in the decision making processes (Bubela T. et al., 2012). This is accomplished by creating an open community that fosters ethical discussion, promotes the exchange of knowledge and actively seeks interaction with the public and the relevant actors in different fields, different socio-economic classes and not only the first but also the third world.

Another essential requirement for the above mentioned global justice is of course the technology. The equitable distribution of benefits and burdens (Bubela T. et al., 2012) is an intrinsic part of justice. It is all too easy to focus on the environmental effects of a project and forget about equally important social factors and distributive justice. Those aspects will become even more important when the question shifts from “Should we release this project in the environment?” to “How should we do this?” and “Is the benefit equally distributed?” We aim to help in the global problem of food shortage in a world with a growing population, but will our system reach those areas where the shortage is the greatest? Our product will have to be cheap, easy to transport and easy to apply if we want to achieve distributive justice. Even cooperation with industries makes it more likely that only they will benefit in the beginning. By acknowledging the importance of distributive justice in synthetic biology, we can ensure that we effectively aid in reducing food shortages and not only increase the crop revenue of those who already have enough.
A possible way to ensure one aspect of distributive justice is by applying procedural justice. All those who will or should benefit and all those who can be adversely affected by our project should have input in the decision making processes (Bubela T. et al., 2012). This is accomplished by creating an open community that fosters ethical discussion, promotes the exchange of knowledge and actively seeks interaction with the public and the relevant actors in different fields, different socio-economic classes and not only the first but also the third world.