Team:Paris Bettencourt/Human Practice/Report


iGEM Paris Bettencourt 2012

How safe is safe enough: towards best practices of synthetic biology



Full Report: File:HumanPractice PB2012.pdf

Please make the report better by adding your ideas to its dedicated wiki: here


In our human practice report, we discussed putting genetically modified bacteria in the wild.

When discussing such a question, it is crucial to differentiate the concerns that are just about synthetic biology and the ones that really involve applications in the field. The debate on the technique should happen, and then be closed once and for all so we can move forward to discussing the applications.

Therefore, we decided to separate our human practice report in two distinct parts. The first one will address the concerns raised by synthetic biology per se, that is, as a technique. Then, in our second part, we will analyze the specific concerns that arise from synthetic biology’s potential applications in nature.

I Debate on synthetic biology as a technique

Firstly, we studied the historical background of synthetic biology. We presented synthetic biology as an extension of genetic engineering, and examined the shared controversies around recombinant DNA technology. We showed that scientists handled the situation in an exemplary way, and we provided a detailed analysis of the 1975 Asilomar conference.

Secondly, we studied the concerns raised by synthetic biology nowadays. We used numbers from the 2010 Eurobarometer on biotechnologies and Hart Research Associates’ 2010 poll on “Awareness & Impressions of Synthetic Biology” to study awareness, perception, and approval of synthetic biology in the European and American populations. We showed that the level of awareness of synthetic biology in Europe is incredibly low (only 17% of participants had already heard of synthetic biology previous to the poll), that the approval rate is low to average in both Europe and the US, that these populations want tight government regulation, and that the main concerns raised by synthetic biology are: unnaturalness, playing god, status of artificial life, potential physical harms, regulations. We then provided a detail analysis of these concerns. We came to the conclusion that:

(a) The “unnaturalness” and “playing God” arguments convey the population’s fear of novelty and of the unknown, and should not just be tossed aside;
(b) Religion is in favor of synthetic biology and does not consider that synthetic biologists are “creating life”;
(c) Questions such as “is there such a thing as artificial life?”, “what will be the status of this artificial life?” will have to be addressed someday, and probably sooner than later;
(d) Biosafety measures to prevent bacteria from harming workers or escaping the lab and proliferating in the wild are efficient;
(e) George Church’s proposal seems to be a good starting point for biosecurity;
(f) Synthetic biology should not be regulated by the free market.

Thirdly, we examined the common question “will rising awareness change anything?”, and its implications. We came to the conclusion that

(a) Skepticism is not necessarily due to lack of awareness;
(b) Education on new technology should be provided so people can be more aware of what is happening around them. Educating middle and high school students could be one way, amongst others, to achieve this goal.
(c) The education on new technologies do not has to be use so that the population can accept them better, only to provide them tools to be able to judge by themselves.

See: Contribution 1, Proposals 1 & 2

II The debate on putting genetically modified bacteria in the environment

Firstly, we examined issues around horizontal gene transfer (HGT), excessive proliferation and risks assessment. We showed the difficulty of assessing risk when it comes to putting genetically modified bacteria in the wild, and that from the very start (beginning of recombinant DNA technology), people have been concerned about HGT and excessive proliferation and tried to create security systems. This is in the spirit of the precautionary principle: “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically. In this context the proponent of an activity, rather than the public, should bear the burden of proof. The process of applying the Precautionary Principle must be open, informed and democratic and must include potentially affected parties. It must also involve an examination of the full range of alternatives, including no action.”(Wingspread Consensus Statement on the Precautionary Principle). We screened the literature and previous iGEM teams’ wikis to identify security systems that had already been constructed. Systems proposed by previous iGEM teams are very often kill switches, toxin/antitoxin systems, aggregation modules, and usually one mutation away from failure. Our literature screen indicated that such systems were used at first, but that scientists then started combining different system (for e.g. two different toxin/antitoxin systems), which made the systems more efficient, but still quite close from mutation. Some more elaborate mechanisms are being created now: they are systems that make synthetic bacteria’s genetic information not universal anymore, preventing communication with wild type bacteria (for e.g. semantic containment, xeno-nucleic acids). We then discussed the master safeguard system we designed to try and decrease the probability of HGT and excessive proliferation. See Contribution 2 & 3

Secondly, we examined other concerns that could be raised by the release of genetically modified bacteria in the environment. We started by doing a case study on GMO plants and crops and looked at the lessons that could be learned, so as not to make the same mistakes when releasing synthetic bacteria in the wild. We concluded from that case study that

(a) Populations want to be informed of what is going on;
(b) They need to perceive some benefits which justify taking a risk;
(c) They want issues like that to be submitted to public debate. And they want the public’s opinion is taken into consideration;
(d) They do not want to feel pressured in anyway by big lobbies to buy things that were created by biotechnology. They want labeling and they want alternatives. They want their right to free choice to be respected;
(e) Some feel very strongly about the fact that industrials are the one funding the scientists to test their products. People would have more trust in an independent comity;
(f) Biotechnology should be used to help the third world, and so research should be oriented in that way too.

We then listed conditions that we find necessary for a responsible release of genetically modified bacteria in the environment:

(a) There should be a real effort to inform citizens on this subject; See Contribution 4
(b) There should be a real dialogue between the general population, the scientists, the politicians and the biotechnology firms. They should agree on goals, benefits, and tolerable side effects. Physical harms, but also ethical aspects should be considered. The dialogue should take place as soon as possible, before too much money is at stake; See Contribution 1bis
(c) Thirdly, no concern should be brushed away before thorough investigation; See Proposal 3
(d) Everyone should be able to benefit from synthetic biology's applications; See proposal 4
(e) Applications of synthetic biology that require releasing in the environment should be tested by an independent comity of scientists; See Proposal 5
(f) The status quo of evaluating projects case-by-case before enabling release in the wild should be maintained

III Proposals

Societal interaction

Proposal 1: We would like that in the future, collaboration with a middle school or high school be a requirement for an iGEM gold medal. This would drastically raise the world level of awareness about synthetic biology.

Proposal 2: Extend proposal 1 to a mandatory high school course called “new technologies”.

Proposal 3: A real discussion with all the actors of society about synthetic biology and its applications.

Proposal 4: We would like to see the creating of a committee similar to the French advisory council for the protection of people in biomedical research (“comité consultatif de protection des personnes dans la recherche biomédicale”), but for biotechnology. It would be called “advisory council on synthetic biology and genetic engineering”. Biotechnologies industries could go and consult this comity before they start the research on the product they wish to develop. This council would take ethical issues into consideration.

Proposal 5: some researchers should work on applications of synthetic biology that can be useful to the third world. We believe that this should be publicly founded. However, the state would get the money through taxing biotechnology firms on the income they make by selling to the first and second world products that use synthetic biology.

Best Research practice

Proposal 6: applications of synthetic biology that require releasing in the environment should be tested by an independent committee of scientists. When an industry wants to test a new product where synthetic biology is involved, it will not be able to test it with its own scientists. An intermediary will have to be involved: the state. The industry will pay a tax to the state, who will, in exchange, ask its independent comity to test the project. We hope that thanks this will relieve the pressure on the scientists to produce results that go in the sense of the industry, as they will not be funded by the industry anymore.

Proposal 7: Safety modules ans risks assessments has to be part of every synthetic biology projects from the very beginning.

We think that safety concerns has to be involved in synthetic biology project at the very beginning, starting from the conception, through design, prototyping, construction, testing and application. This is because of the interdependence of different parts and modules in a synthetic biology project. Once a device is designed, built and tested, new features and concerns are hard to implement without changing previous stages. Thus instead of designing for a successful outcome and then add safety concerns, it will be much more efficient and less risky to design for both successful outcomes and potential failures.

We experience first-hand the need for such a mindset. Our project started as a time-controlled enzyme-releasing device that involve a series of restriction-enzyme expression and DNA digestion. After the initial design, we realized it is a sort of "rube goldberg machine" that will work in an ideal situation, but is prone to failure to mutation at every step and will introduce undesired live genetic-modified microorganisms into the environment. This realization completely changed our approach and design principles. The focus is no longer how to realized the intended behavior - releasing a specific enzyme, but how to avoid undesirable outcomes - releasing either live GMO or potentially harmful DNA sequences.

Simple back-of-the-envelope calculations can be done even before any experiment are done. Usually the risks of system failure can be assessed from two perpectives. One is the complexity and redundancy of the system. The more complex and less redundant the system is, the higher the risk of failure. The other is mutation and evolution. One should assess the population size, lineage structure and mutation rates of the devices thus the likelihood of having mutants, and selective advantage of those mutants might possess against both the intact strains and organisms in the wild.

Proposal 8: Each synthetic biology application should assess and disclose a list of application specific risks and hazards.

After a set of safety mechanisms has been proposed in our projects, we realized there are no absolute measure of safety. All measures of safety are relative, and depend on applications, contexts and environments. Thus safety standards and disclosure of potential hazards can not be left to safety specialists, but be specific to the application. The designer and builder of devices have to assess quantitatively the potential risks and disclose such results, similar to the Material Safety Data Sheet approach. These information should be considered as part of the characteristics of the product. Only with such information, the policy-makers and the general public can make informed decision.

Proposal 9: The community has to build a collection of bio-safety devices for future engineers.

Since safety concerns are crucial to the success of synthetic biology, an organized effort should be made to collect and standardize safety devices already present. This is apparent from our survey of past iGEM projects: many teams had considered safety, designed or made safety modules from their projects, they vary in terms of applicability and efficiency, and lack diversity in terms of mechanisms. In the spirit of iGEM, we published the results of our survey in our wiki. We hope more extensive efforts can be made in this area so that future engineers can match the potential hazards of their applications to existing safe guard devices, or identify missing critical safety mechanisms to be included in their projects

Proposal 10: Development and adoption of a safety chasis for synthetic biology research and prototyping.

Besides the heavily regulated real-world applications of synthetic biology, research results about synthetic biology safety can be applied to laboratory research and prototyping. In accordance with the iGEM idea of standardization and modularity, simply incorporate some known safety features into the genetic background of the most commonly used standard chasis can go a long way in improving safety in the whole synthetic biology community. For example, in commonly used E.coli strains, cpxAB mutants are known be deficient in horizontal gene transfer by conjugation [1]. The widespread adoption of a chasis with such a mutation and other safety features, in the background would reduce unintentional risks and improve general safety in the research community in addition to all the safety precautions people already took.

1. McEwen, J. & Silverman, P. Chromosomal mutations of escherichia coli that alter expression of conjugative plasmid functions. Proceedings of the National Academy of Sciences of the United States of America 77, 513-517 (1980).

IV Contributions

Societal Contribution

Contribution 1: We organized a workshop on synthetic biology for high school students in order for them to discover this new field. We also gave them a tour of our lab.

Contribution 1bis: Here, we decide to take the contribution 1one step further. After the introduction to synthetic biology, we would discuss with students what they would consider as benefits and acceptable risk. This would take the form of discussing synthetic biology projects they brainstormed. See wiki page on the workshop for additional details.

Contribution 2: We organized a debate involving 10 university students from very various background (law, politics, etc), but no one studying synthetic biology. 70 people came to see the debate. They had to debate on the following motion: “This house would allow environmental release of genetically modified bacteria for applications in the following fields: medicine, pharmacy, agriculture, energy, bioremediation”. 5 students were assigned to be for, 5 students were assigned t be against. They had one week of preparation. We were impressed by the level of the debate. See the debate page for further details.

Best research practice

Contribution 3: We tried to engineer a master safeguard system. We wanted this system to be as robust as possible against mutations. We decided to add up containment systems in order to increased robustness. We relied on three levels of containment: - Physical containment with alginate capsules - An improved killswitch featuring delayed population-level suicide through complete genome degradation. - Semantic containment using an amber suppressor system We acknowledge that our system is not perfect or infallible. However, we believe that it is a good starting point, and that next year, teams can build up from this like we built up from previously existing systems.

Contribution 4: We created a safety page on the registry. Teams can put the safety circuits they created there, and assess its efficiency. In the future, we would like that the standard plasmids contain safety elements (for e.g: autodestruction system, etc). Our aim is to promote safety in future iGEM projects.

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