Team:ULaval/Human Practices




Human Practices
Introduction

In 2016, the price for a portable EpiPen® kit (two syringes, each containing one dose of adrenaline) increased abruptly in the US, from $100 US to $500-600 US1. The shortage of the drug and its high price led to a reduced accessibility. Adrenaline being the drug of choice for the first-line treatment of anaphylactic shock - adrenaline is injected intramuscularly by the patients themselves if they owns a portable kit - its reduced accessibility raised concerns among parents, who cannot provide enough portable kits for their children, as well as patients and physicians. This widely mediatised issue raised our attention and prompted our cogitation on the possibilities to help render adrenaline more accessible by mean of synthetic biology.

The AdrenaYeast project aims at producing adrenaline using the baker yeast, Saccharomyces cerevisiae. Adrenaline is considered essential and insufficient in all the countries recently investigated by the World Health Organisation2, 3, 4.

Furthermore, the current manufacturing processes to produce adrenaline use chemicals that may be harmful to the environment and human health5. The biosynthesis of adrenaline in yeast might help avoid these important issues. Whether the biosynthesis of adrenaline in yeast will reveal a less expensive technology than the current chemical synthesis awaits for a techno-economic analysis. If so, our procedure may help render adrenaline more accessible to developing countries, as is the case with the antimalarial drug artemisinin6.


What are the issues related to the biosynthesis of adrenaline?

We are aware that the AdrenaYeast project will face challenges. As a biotechnology-based health product, yeast-produced adrenaline will be subject to rigorous regulations to prevent any possible health risks. In Canada, any therapeutic agent developed by means of genetic engineering is regulated under the pre-market review and approval standards of Health Canada for new drugs7. The only way to guarantee its safety requires testing its purity, identity, sterility and stability. After proving that biologically synthesized adrenaline is identical to chemically synthesized adrenaline, clinical trials will be conducted to prove its safety in humans8. However, our present concern is to achieve our proof of concept. In other words, we want to, first, demonstrate the feasibility to produce adrenaline in yeast in sufficient quantity before considering its industrial potential.

Additional challenges will need to be addressed such as optimizing the adrenaline production by reducing byproducts and maintaining constancy of quality and quantity. Nevertheless, microorganisms are nowadays used in so many different ways: in the food industry, to produce beer, cheese and yogurt as well as for food preservation9. They are also used in healthcare, to treat intestinal diseases such as Crohn's disease10 or to perform gene therapy using viruses11. This plethora of applications implies that it may be difficult to preserve constancy of a microorganism’s products. It is, however, not impossible.

In addition, we must investigate how our yeast-produced adrenaline would be perceived by the public. Indeed, people are generally concerned by genetically modified organisms (GMOs). Being confronted with the choice to use a biologically synthesized medicine would be quite new for a great deal of people. In order to avoid patient’s hesitation during an emergency situation involving the use of adrenaline produced via this new method, we deemed important to investigate the social acceptance of GMOs.

Scientific research is not only about science, it is also about its impact on the society and environment. To better understand the bioethical aspects of our project, we met with a philosophy student, François Champagne-Tremblay and an ethic teacher Jean-François Sénéchal at University Laval. They brought to our attention possible repercussions of our research and helped us design a survey to gather public input on the various implications of our project. Our survey contained questions about ecology, economy, ethics and society. It was designed in the most objective way. It also aimed to educate respondents on synthetic biology. Moreover, we exchanged ideas about important issues regarding synthetic biology with two other iGEM teams, Toulouse-INSA-UPS and NUSGEM (Singapore Team-A). We first discussed different topics including ethics, environmental impact, public engagement and repercussions on the public life. Then, we decided to write a report on the three main topics selected: bioethics in synthetic biology; economic aspects towards synthetic biology; and society’s perspective of synthetic biology. Finally, we talked about our project on social media, in university classes and we had a radio interview to present our project and bring science to the public.


In order to fully understand the ethical challenges of our project, we had to go beyond our comfort zone. It is important to see further than the results we wish to obtain. Luckily, we had the chance to talk about AdrenaYeast with an ethic expert who also has a background in transgenic studies. In fact, Jean-François Sénéchal is a teacher of ethical science in the Department of Philosophy at Laval University12.

In addition, in order to have an unbiased point of view on the subject, we decided to also ask the opinion of someone who had no or very little scientific knowledge. Therefore, we interviewed an undergraduate philosophy student, François Champagne-Tremblay, whom we thought could answer our questions about the safety of our project as well as our responsibility towards the public.

Our capacity to predict events is limited to our knowledge and we cannot predict all the possible consequences of our project. In the following sections we tried to answer all the questions raised by the people we interviewed as best as we could.


Meeting with the Ethic Teacher

We discussed several ethical aspects that shall be considered throughout the different stages of our project. The teacher brought to our attention the safety issues related to our project and our responsibilities towards the industry and the patients. For example, could there be any health risks? If our product is to be sold in drug stores, should it be labeled as a GMO derived medicine? If it is indicated, will people understand what it means?


The steps we intend to do by ourselves to prove the identity of our product

We must verify the identity and the purity of our product in order to confirm that we achieved the production of adrenaline. In addition, since adrenaline is synthesised biologically, unexpected chemical modifications may occur. Therefore, the adrenaline produced could be different from that expected. We planned to purify yeast-produced adrenaline by HPLC and to confirm its identity by mass spectrophotometry and nuclear magnetic resonance spectroscopy.


Potential Impacts for Health

As explained earlier, in Canada, any therapeutic agent developed by means of genetic engineering is regulated under the pre-market review and approval standards of Health Canada for new drugs. Therefore, the health risks should be minimal. However, for ethical considerations, we also listed every potential causes of chemical impurities, immunogenicity or lack of sterility, even including those that seemed impossible.

Introducing a new metabolic pathway into yeast cells could have major impacts on the other metabolic pathways and undesired products could be synthesized for instance. For any reason, our molecule could trigger allergic reactions in some patients. In addition, our final product could be harder to purify than when produced chemically. In order to sell our yeast-produced adrenaline, there would be a need for a serious investigation of its purity and the methods taken to prove it.

We also considered the possible production of enantiomers. Indeed, the chemical synthesis of adrenaline results in a racemic mixture of the R and S enantiomers. The R enantiomer, which is biologically more active13, must be purified by chiral HPLC chromatography. This additional purification step increases the production costs. Unlike the chemical procedure, the biological synthesis can only produce enantiopure molecules as enzymes are enantioselectives14. Since we inserted human DNA into our yeast, we expect them to produce only the biologically active R-enantiomer of adrenaline. However, we still intend to investigate the presence of an additional enantiomer by chiral HPLC chromatography.

Adrenaline is a hormone used in medicine to treat cardiac arrest, anaphylactic shock and some serious shock conditions (ICU). It is toxic even in low concentrations (subcutaneous, LD50 0.007 mg/kg15). Pure adrenaline can be lethal if in contact with the skin or if ingested16. The wearing of personal protective equipment is thus required during laboratory work including the synthesis and purification of this molecule.


Transfer of Responsibilities

Another aspect discussed in this meeting was the transfer of responsibility for our product to the industry. Responsibility is the duty to answer for one's actions, all circumstances and consequences included, that is to say, to assume the enunciation, the execution, and consequently the reparation or the sanction when the expected is not obtained17. Therefore, “the responsibility is the consequence of the competence because it is to answer for its acts in the presence or not of a fault in the exercise of its competence”18. This means that if something serious happens, those who assume the responsibility for it are held accountable. We must ensure that there will not be consequences if we transfer our responsibility to another company and that we thus cannot be held responsible.


Consent

Finally, we discussed patient consent in the context of immediate need of adrenaline injection as well as when prescribed. It is important for a patient to know the medication he is being administered and where it comes from. This means that patients who could use adrenaline produced using synthetic biology should be informed on its synthesis. We think that we should create, with the help of a legal team, a consent form, informing patients of everything they need to know. This form could be distributed by the pharmacist or the physician before the patient buys the product. In the event of an emergency requiring an immediate injection of adrenaline, the person administering it should be held responsible if the patient does not wish to receive this product and has clearly expressed that wish.


Meeting with a Philosophy Student

After our meeting with Jean-François Sénéchal, several questions remained unanswered about the safety of our project and the repercussions on society. Therefore, we decided to meet a philosophy student, François Champagne-Tremblay, to get the point of view of an uninitiated person. After an hour and a half trying to explain our project in the simplest possible way, we came to the conclusion that it would be difficult, if not impossible, to get answers from someone who does not even know what yeast is. Towards the end of the interview, we had raised more questions than we got answers.

For François, synthetic biology is a technical progress and, as for other technical progresses, the following questions should be asked: Is there a danger to health or the environment? Are waste produced and how will they be managed? What are the impacts of technology on the economy and society? All of these questions led us to a bigger question: Is the sum of the negative impacts greater than the sum of the positive impacts? In other words, is it really worth it?


Potential Environmental Impacts

Currently, the behavior of synthetic biological systems remains unpredictable19. It is also unknown how synthetic biological systems will evolve. In most cases, biological systems engineered by scientists quickly recover their initial phenotype (i.e., they lose their engineered function instead of acquiring a new one)20. Although this notion may seem reassuring, it does not exclude the possibility that those systems might evolve in unpredictable and harmful ways, particularly if spread outside the laboratory.

Hormones can have a significant impact on the aquatic life and can even end up in drinkable water after treatment21. To prevent the risk of spreading hazardous biological entities into the environment our yeast must contain a “kill switch” or any other mechanism to control its proliferation22.

From a sustainable developmental perspective, we hope to develop a more ecological process than the one offered by the chemical synthesis of adrenaline. For example, the biosynthesis of adrenaline would likely necessitate less water as well as no solvent or other toxic chemicals. However, the ecological footprint of each method must be calculated to determine which method is the most environmentally friendly. The extent of the infrastructure needed for each method should also be determined.


Waste Management

Waste produced by a fermentation process are composed of dead cells and co-fermentation products such as CO2 (gas) and organic compounds. There are many ways to eliminate these products: incineration, if dangerous products such as adrenaline23 remain; bioconversion of organic waste24; and irradiation or pasteurization to kill remaining living cells25.


Economic Impacts

The most important benefits of synthetic biology are related to health, energy and the environment. Nevertheless, investments in synthetic biology can also bring economic benefits. For example, direct activities related to research and development and the potential commercialization of successful technologies are likely to create new jobs and improve the economy, thereby improving the overall quality of life of the population. In addition, these potential economic benefits can be particularly useful for communities in developing countries, where health, access to resources and economic stability are closely linked.

Furthermore, it is essential to assess the competitiveness of synthetic biology in relation to other existing industries (e.g. chemically synthesized products). In our case, adrenaline synthesis is currently made chemically. If the biosynthesis of adrenaline is proven to be less expensive, more environmentally friendly and more easily accessible in terms of equipment, it could, in this case, disrupt the current sector. In addition, it could disrupt monopolies by creating smaller businesses. It could also mean that adrenaline, an essential medicine, would be more available in developing countries. However, if our technology was taken by a large enterprise, it would bring us back to the same problems associated with a monopoly.


Impacts on Society

Overconsumption is an important issue to consider when talking about drugs. Medicines should never be used for recreational purposes, but still, there will always be someone, somewhere who wants it for that reason. As mentioned previously, adrenaline is a deadly compound and it should not be used by someone who does not need it. However one might see the opportunity to use this drug in the context of the black market. Indeed, adrenaline can be used by drug users to treat overdoses of other drugs such as heroin.

Ethically speaking, can creating the abundance of a product lead to its abuse? In our case, we would not tend to think so mostly since the purchase of adrenaline requires a prescription. However, one must wonder if it could be used by people who do not need it for medical purposes, like adepts of extreme sports who consider themselves “adrenaline addicts”.

On another note, the metabolic pathway of adrenaline includes the intermediate dopamine from which it is possible to synthesize opioids such as morphine26. With in-depth knowledge, material and extra work, it would, therefore, be possible to use our system to synthesize these opioids for resale on the black market or for recreational use.


Do benefits outweigh the risks?

Every development in science can have consequences, on health, environment, society, economy, religion and more. The purpose of bioethics is to study the ethical issues related to biology and medicine. Our main concern about bioethics with our project is about biosecurity because adrenaline is already an existing medicine. The National Science Advisory Board for Biosecurity (NSABB), an independent federal advisory committee charged with advising the U.S. government on biosecurity issues and “dual use” research - that which may be used for either good or ill - defines the term as follows: “biosecurity refers to the protection, control of, and accountability for high-consequence biological agents and toxins, and critical relevant biological materials and information, to prevent unauthorized possession, loss, theft, misuse, diversion, or intentional release”27.

There are two opposing principles regulating actions in the area of synthetic biology: the “proactionary principle” and the “precautionary principle”. They range from doing nothing - that is, allowing the field of synthetic biology to proceed without limits or regard for public or environmental safety - to halting or substantially slowing its progress until risks can be identified. The “proactionary principle” also assumes that an emerging biotechnology should be considered “safe, economically desirable and intrinsically good unless and until shown to be otherwise”28. Those are both extreme measures and a middle ground would be an ongoing system of “prudent vigilance” that carefully evaluates risks of harm along with benefits.

Responsible research calls for prudent vigilance, establishing processes for assessing benefits along with safety and security risks both before and after projects are undertaken, and as technologies develop and diffuse into the public and private sectors. Scientists have been conducting biological researches that pose risks throughout the history of modern science. Over time, safety and security procedures have expanded and evolved to increase the likelihood that risks will be anticipated, mitigated, and monitored and that responses can be activated quickly should harmful consequences arise. These principles allow for the well-being of the communities today and, more importantly, of future generations.

All this considered, responsible science should reject the technological imperative: the mere fact that something new can be done does not mean that it ought to be done. Nonetheless, we believe that our project can have a great deal of positive impacts on the environment, society, economy and science, thereby outweighing the risks.


Following our meetings with François and Dr Sénéchal, we realized that we could not have a truly objective opinion only by interviewing two individuals. We concluded that it would be best to conduct a survey in order to obtain the opinion of a larger public to answer our questions.




The majority of respondents are undergraduates from Canada and Europe and are millennials.


Most of them have a high level of knowledge in biology and connected fields. This answer was expected since the survey was mainly shared on the social media pages of the members of our team and sent out to other iGEM teams. However, we were glad to see that there was still a considerable portion of the respondents who only have a basic knowledge in biology because we constructed our survey in order to educate people about synthetic biology.
Of all respondents, about 80% already knew before taking this survey that adrenaline was an essential medicine, even if only 56% knew at least one person who owns an EpiPen® (including themselves). Less than 10% thought that adrenaline is only used in EpiPen® to treat allergic reactions or did not know what it is used for.
Biological VS Chemical
At the beginning of our survey, before giving any information on biological and chemical synthesis, we asked respondents what they would prefer between adrenaline synthesized biologically and chemically.

At first, most people answered that they had no preference as in both cases the molecule is the same and in times of need they would not mind which one they are injected with.


After the survey, some people found out that they were wrong about what “biologically made” means and realized that it is not as natural as they thought. Therefore, they switched for “No preference” instead of “Biological” since they felt that they needed more proof that synthetic biology is safe for the health and environment.

On the contrary, some people who first answered “No preference” switched for “Biological” as they realized that synthetic biology can have many advantages.

No significant changes were observed within the other two categories.


Our survey had an important impact on our respondents’ opinions. Some learned about potential benefits they did not know about and some were not convinced of the safety aspects, but in the end they all learned something about synthetic biology and maybe we piqued their curiosity about that field.
Shortages
We informed respondents about a recent shortage of EpiPen®. We wanted to know their opinion about the price increase of an essential medicine in the event of a shortage. The majority answered that the price increase is not justified since it is an essential medicine and everyone should be able to access it when needed, the rich and the poor. Also, they suggested that quotas would be more appropriate than raising prices.

A considerable fraction of respondents answered that it is justified to raise prices of medicines as they believed that it represents a good way to prevent overconsumption. In a marketing perspective, it was also mentionned that it is simply the principle of supply and demand.


Overconsumption


Since we think that our technology could make adrenaline more accessible, we were concerned about the possibilities of overconsumption. Because there is a low probability of abuse of adrenaline, we asked respondents about the overconsumption of any medicine in the context of a lowered purchase price. There is an important disparity over that question because many people believe that it is impossible that others will abuse of certain medicines.

However, when they are asked if they would themselves abuse of a medicine if they could, 96% of respondents answered that they would not. Nonetheless, about 10% of those who said they would not abuse of drugs said that if the prices dropped they might buy more to make stocks.


One respondent commented: “I would not use more than before necessarily, but if I’m a long-term patient and see it for cheaper, I’m likely to buy in bulk (depending on the conservation of the drug) and consume in the same dosage as needed before. This could be avoided if the drug is under prescription, legally sold only in small quantities or made to require very specific conservation conditions (e.g. very low temperatures) that would be difficult to achieve in a common household for a long period of time. Better strategies for drug conservation could also mean that the drug would be more available globally, but it does not mean that it has to be overconsummed.”

On the other hand, some respondents commented that one should not buy more of a medicine just because it is cheaper, saying that it is not like pizza or toilet paper.

Are GMOs worse than chemicals?
The large majority of respondents (93%) chose GMOs over the chemical production of adrenaline. Half of them considered GMOs not harmful in any way whereas the other half were not so fond of them, but still considered chemical synthesis even worse. Finally, only a few respondents (4%) thought that GMOs are worse than the chemical production of adrenaline.

The results show acceptability of GMOs throughout our respondents, but it may be due to the academic background of the respondents. Indeed, a large proportion of them have a high understanding of biology and have heard of genome editing prior to taking this survey. Thus, our results could be biased.


The risks of synthetic biology

Since most of the respondents were informed about biology, we asked them if they could come up with some risks about synthetic biology that we did not identified ourselves.

Here are the most frequently identified health risks:
- Risk of mutations in the modified yeast that could result in the production of toxic alternative products. (16 respondents) - Side effects that could occur on the human body. (12 respondents) - The preservation and stability of the compound while stored or transported could be different than the chemically produced adrenaline. (9 respondents) - Contamination from other microorganisms. (7 respondents)

Concerns about health risks were more frequent, but many economic and technical concerns were also raised:
- Is the adrenaline stable during the extraction process? (1 respondent)
- Is there a molecule produced on the metabolic pathway that is toxic for the yeast itself? (1 respondent)
- Could an another industry make something out of it? (Energy drink / Beer / Sell it on the black market) (9 respondents)

What is natural?

We constructed our survey in order to educate people about synthetic biology and GMOs, and to trigger ethical reflection about what is natural. In this section, we explained how "natural" is a complicated and often subjective word. Indeed, it is often used as a metaphor to mean good and healthy. In our survey, we explained how it is hard to define “nature” or “natural” in the context of industry, particularly in light of humans’ long history of interaction and effect on other species, humankind, and the environment29. In other words, according to some people’s definition of natural, even farm animals and plants cannot be considered natural.

We then asked respondents to rate their perception of natural from 1 to 3 (see chart on the side). As you can see, the large majority of respondents answered that natural means “found in nature in its raw state”. After that, we asked them if they considered our yeast-produced adrenaline natural and the answers were quite divided.





When pooling the answers to these two questions, we find that those who consider our adrenaline natural are mostly those who think that natural means “assembly of natural products” and vice-versa. In other words, their rating of naturalness in the previous question directly corresponds to their perception of the naturalness of our product.



In conclusion, our survey helped us realize the need for popularized science as many people fear what they do not understand. Scientific progresses affect everyone but those who fear the progresses may oppose it. Therefore, opportunities for the public to participate in discussion and deliberation about emerging technologies such as synthetic biology are critical. In order to communicate properly with them, scientists need to popularize their work and engage debate over sensitive topics. A further analysis of this topic is presented in the next section.



Introduction

From crops to cattle to dogs, humans have always sought to improve their living conditions by adapting plants and animals of their surroundings to their needs[1]. However, these occur over a lengthy selection processes over hundreds, possibly thousands of years. New developments in the field of biology has enabled us to progress much faster, by interfering with an organism’s DNA directly.

Synthetic biology is an emerging scientific and biotechnological field that uses these developments at its core. It combines biology and engineering principles, with the aim of designing and building new biological systems and functions.

Synthetic biology has been gaining interest among ambitious science students who are seeking to bring their research outside the lab and be involved in more application-based solutions. The International Genetically Engineered Machine (iGEM) competition brings together thousands of students across the globe to develop synthetic biology solutions and collaborate with one another based on the common passions.

Among hundreds of teams that participated in this year’s event, Team Toulouse-INSA-UPS, Team NUSGEM (Singapore Team-A), and Team ULaval came together to exchange ideas about relevant issues regarding synthetic biology. Before writing this report, we discussed different topics ranging from ethics, environmental impact, public engagement, repercussions on public life, and more. We chose three main subjects to discuss: bioethics in synthetic biology; economic aspects; and society’s perspective of synthetic biology.

Bioethics in Synthetic Biology (Toulouse)

A lot of factors have to be considered when evaluating the benefits and risks of using synthetic biology. To develop a new production method for example, one must first closely study the available techniques that do not employ synthetic biology. If something can be produced chemically, then a comparison has to be established between this process and the potential new synthetic biology based process. Once this comparison is made, and if synthetic biology can offer an advantage (less costly, quicker, more environmentally friendly, etc), then it is sound to develop a new method based on synthetic biology.

The process of bringing a new product from the lab to the market will often result in the oversimplification of technical knowledge and the associated ethical considerations. People who are involved in this process, be it a businessman or a policymaker, should, in our opinion, be aware of issues that emcompasses the use of synthetic biology in their products. One area that is especially important to talk about is bioethics. A discussion about bioethics can help society define both possibilities that are welcomed and boundaries in which society should remain.

The advantages brought by modifying living organisms are far from minor[2]. Here, we will take the example of two industries central to this field: the pharmaceutical industry works in the medical sector and aims to improve the daily lives of suffering patients, while the agri-food industry seeks to feed the world, and the optimisation of its yields may seem secondary in comparison to pharmaceutics. However, the human population is ever growing, and feeding billions more mouths may become a more pressing problem than what we may first think.

In these two major areas, the synthetic biology industry is making great leaps forward and enabling innovations that directly affect society. The first is the creation of new medicines and skincare techniques that could improve the quality of life for everyone. The second is to increase the profitability of certain foodstuffs, which could help reduce hunger in the world.

Take the example of Taxol: it is a cancer chemotherapy agent, acting on spindle stabilisation. Its effects are proven on cancer but remain very inaccessible to many because of its price (about 6000 USD for a full cycle[3]). The reason behind the high cost is the inefficient extraction process from the Pacific yew tree that produces not only low yields of Taxol, but also impure mixtures of compounds. By going through a synthetic biology process, we can simplify the production and purification process. The cost of this drug could then drop dramatically[4] and therefore be much more readily available to those who need it.

Similarly, allowing the creation of plants for continuous food production regardless of the season would result in a significant cost reduction of food which could reduce hunger in the world. This raises the issue of the spread of this technology in the environment, which remains a major problem. Through the spread of artificial products, some ecosystems could become seriously threatened, and maybe even face disappearance. Humans introducing foreign species into different environments has, historically, not gone well, as the Australians can tell you regarding rabbits[5]. Introducing a species which is genetically engineered to be more resistant to harsh temperatures or produce more seeds could therefore lead to even greater problems.

The question to ask ourselves here is no longer “can we achieve this?”, but rather “should we achieve this?”. We have ventured into the technology necessary to modify living beings to our design, creating new subspecies in our free time. We must now study with intense scrutiny the impact of our actions and the moral justifications behind them.

The prospect of developing more efficient antibiotic formulations might seem attractive, yet the reckless and unregulated use of antibiotics will soon spawn new strains of resistant bacteria, harbinging a storm of more drug-resistant infectious diseases. Unfortunately. the current state of matters leads to the very distasteful and unpalatable consequence of breeding drug-resistant pathogens. Effects of these drug-resistant pathogens places undue pressure on the pharmaceutical industry, for the Sisyphean task of developing newer antibiotics to keep up with the development of stronger drug-resistance.

As the saying goes, prevention is better than cure - we strongly believe that judicious usage of the available classes of antibiotics, coupled with vigilant antibiotic stewardship programmes in healthcare settings, should become more commonplace. The fearsome tragedy of having no available antibiotics for treatment, such as in the case of carbapenemase-resistant Enterobacteriaceae, harkens back to the Dark Ages before the discovery of antibiotics, and must not be allowed to catch us off guard.

Once we have our priorities settled, even more important questions need to be asked. Is modifying the human genetic code different to modifying that of the plants and animals around us? Again, the risks and benefits require heavy evaluation. Fixing a deleterious mutation causing diabetes or multiple sclerosis could change someone’s life, but deciding what your child’s eye colour will be is probably going too far.

To conclude, it is safe to say that these new developments are not much more different than others before it. Humanity has caused a great deal of damage to the environment through greenhouse gases and deforestation, all for the sake of ease of life and financial profit, to cite only one example. While synthetic biology affects a more profound basis of life, the leaders of any scientific revolution must always reflect on the impact that it will leave on the world before declaring that we are living in a brave new world.

Economic Aspects towards Synthetic Biology (NUS)

For some, genetic engineering is akin to playing God. However, to many synthetic biologists and life science researchers, genetic engineering is a key pathway to exploring a plethora of new applications and technologies. Unfortunately, few of such technologies have been successfully commercialised. Yet, for these select few, they are largely disruptive in their own fields.

To illustrate this point is the development of the antimalarial drug, artemisinin. Artemisinin was first extracted from Artemisia annua, or sweet wormwood, in the 1970s[6]. Since then, global demand for artemisinin has only increased, especially after 2001, when the World Health Organisation identified artemisinin-combination therapies as the recommended first-line treatment for malaria[7]. Yet, the supply of artemisinin remained variable due to the limited cultivation of sweet wormwood, which in turn translated to fluctuating and volatile costs of artemisinin-combination therapies. The vagaries of the artemisinin supply inspired several companies and researchers to set about developing novel alternative methods for the synthetic production of artemisinin to complement plant-derived sources. Sanofi, a Paris-based pharmaceutical company, for example, employed the use of a genetically-engineered yeast that used glucose as a feedstock, to produce artemisinic acid, a precursor of artemisinin[8]. This genetically-engineered yeast was also simultaneously “engineered” by Jay Keasling, a researcher at the University of California (Berkeley), who also developed the chemical pathways necessary for the successful bioproduction of artemisinic acid[9].

The advantage a synthetic biology-approach of artemisinin production provides, such as cheaper and more stable source of artemisinin, is clear. However, the concerns arising over synthetically-produced artemisinin (which manifests as market resistance), such as the monopolistic behaviour of pharmaceutical companies, and the loss of livelihood of the Artemisia farmers, must not be ignored. The balance between novel technologies, and its social and ethical implications must be carefully considered - is synthetic artemisinin really cheaper? How can synthetic biology help the farmers whose livelihoods have been disrupted by a decrease in demand for sweet wormwood? How can synthetic artemisinin be responsibly produced and consumed? Without giving due thought and consideration to the existing methods of artemisinin production, it would be a travesty and tragedy to brashly impose synthetic artemisinin on all its consumers.

Drugs aside, there are currently exciting ongoing research involving the food industry. Biotransformation is a multidisciplinary platform within A*STAR focused on developing microbial fermentation processes to produce high value ingredients more sustainably[10]. By using microbial and synthetic biology methods of producing ingredients, food production becomes less land and weather dependent and in higher quantity. A similar case in chemical manufacturing is the story of truffle oil. Truffle oil was previously available only through foraging of truffles, which are also seasonal. However, with artificial truffle oil in production since 1980s, constraints on quantity and seasonality have been greatly removed or eliminated[11]. Synthetic biology is also actively applied to other fields, leading to the development of potentially transformative applications, such as in therapeutics and biomaterial production. For example, in California, at the startup Bolt Threads, spider silk is produced using genetically engineered yeast[12].

A major obstacle preventing widespread adoption of these novel synthetic biology-based technologies is economic feasibility. Yield is a common problem affecting many new bioreactor fermentation and bio-manufacturing processes. As engineered cells are not naturally inclined to produce the intended products, doing so induce metabolic burden. increasing yield must therefore be achieved by balancing against cell metabolic stress due to production. Furthermore, semi-biologically produced drugs and compounds are larger than chemically produced ones, presenting production challenges and keeping costs high. In large-scale bioreactors, due to the time taken for the diffusion of substrates, heterogeneous conditions between different parts of the bioreactor can create different kinds of reaction conditions and different stresses for different cells. This variability makes bio-manufacturing more expensive and unpredictable. Lastly, for drug production and quality control, the conditions for protein 3D-folding also makes it susceptible for viral contamination[13].

Nonetheless, the global bio-based market remains a growing market with high potential, driven by synthetic biology[14]. It is anticipated to reach US$38.7 billion by 2020, based on predictions by market research company Allied Market Research[15]. Governments all around the world, from the United States to China, are increasingly acknowledging the immense potential of biotechnology, and are increasing investments in an effort to develop biotechnology and its related fields. China, for example, has identified synthetic biology as one of the priority research areas of the country, and its Ministry of Sciences and Technology has invested heavily in funding schemes and initiatives concerning synthetic biology. Perhaps more convincingly the importance the Chinese government places on synthetic biology development, synthetic biology was recently identified as a key industry for China’s Five-Year Plan (which was recently published in 2016)[16].

Singapore (a notably different country from China) has similarly invested $25 million (about USD 18.2 million) in its recently-launched “Synthetic Biology Research and Development Programme”, which includes groundbreaking projects ranging from exploring uncharted biosynthetic pathways for the production of medical cannabinoids, to engineering microorganisms that are able to convert readily available and renewable substrates into valuable organic compounds. In 2015, Singapore set-up its first research centre dedicated to synthetic biology, SynCTI, at the National University of Singapore with the aim of anchoring Singapore as a leading Synthetic Biology Hub in the world. In 2016, the Singapore Consortium for Synthetic Biology, SINERGY, was launched in order to create a vibrant and globally connected bio-based economy in Singapore [17].

Likewise in Australia, where the Australian Council of Learned Academies recently published a outlook report on the prospects, opportunities, and issues associated with synthetic biology [18]. Synthetic biology was identified as critical to Australian economic development - from complementing and supporting the continuous growth of industries in which Australia has been traditionally strong in, i.e. agriculture, to providing new opportunities for further research and development, in the fields of health and medicine, and the environment. The focus on synthetic biology has been welcomed by the Australian government, whose Research Infrastructure Investment Plan supports research initiatives and studies into synthetic biology.

Compared to chemically synthesized products, bio-manufacturing offers a competitive advantage for producing products that are both economically viable and ecologically sustainable. An appealing option nowadays, as both consumers and governments are changing consumption patterns and policy regulations to take into account the negative externality that is environmental pollution. An example of the competitive advantage in environmental sustainability that synthetic biology can offer is optogenetic regulation. This new tool in synthetic biology provides the potential to eliminate chemical-dependent control, removing the carbon footprint from chemical production and waste treatment and further enhancing its environmental sustainability.

Synthetic biology is an emerging market with many techniques and tools that have yet to mature[19]. Strong governmental support is required to aid in the development of this market, but current signs for its development are promising. Recent start ups such as Zymergen and Ginkgo Bioworks have experienced explosive growth and are making big waves in the synthetic biology industry. Synthetic biology itself has shown potential for high applicability in various different fields. Nonetheless, the development of new technologies, as always, requires acceptance and support from society.

Society’s perspective on synthetic biology (ULaval)

Genetic engineering impacts society in a wide variety of ways, ranging from pharmaceuticals to crops to. However, people are often unaware that their food or medicine has been produced by mean of synthetic biology. Perhaps, provided with this knowledge, they would reject such products because they might be afraid of what they do not understand. In this section, we attempt to explore and elucidate the following: Is the society knowledgeable enough about biological synthesis and genetic engineering? How can they be better informed? How accepting is the general public towards GMOs? Who are the opponents to this technology?

Fear is often closely linked to ignorance[20]. As of today, synthetic biology still remains an emerging field, but in the past has often be portrayed as a dangerous thing, especially in popular culture. One of the best known is Jurassic Park, in which scientists succeed in bringing dinosaurs back to life using genetic engineering. While people with a scientific background can generally identify the line between science and fiction, some science fiction writing can appear convincingly real to the uninitiated.

Because of this, synthetic biology has often frowned upon, even considered “dangerous” to health and the environment, despite approvals by regulators and scientists, and their benefits recognized to date, with examples like biofuels[21] and increased yields and agricultural growth[22]. To prevent misconceptions, the scientific community has to invest more time to popularize synthetic biology, and educate and inform the public to allow them to better understand how GMOs are designed and function.

Public scepticism towards new technology is not unfounded. Indeed, scandals in the recent history of the scientific community have put a damper on the credibility of some scientific studies[23]. Disasters in healthcare, like the prescription of tobacco as an anti-stress medicine[24] and the tragedy over the prescription of thalidomide to pregnant women[25], or other cases like the mad cow disease[26] are good examples. While healthy scepticism is important, it must not be confused with anti-intellectualism. In the US, there is an increasing group who mistrust experts[27] on important matters such as global warming and the general unequivocal consensus by the scientific community that global warming is man-made. Public scepticism is one of the factors delaying the much needed development of more environmentally sustainable technologies[28].

To counter this slowdown, education is critical. In order to communicate about and debate sensitive topics, scientists need to popularize their work. Popular science is closely linked to the acceptance of scientific progress, and is part of researchers’ missions[29]. It represents the bridge between scientific literature and popular knowledge. Meaningful citizen participation in deliberations regarding synthetic biology requires familiarity with general concepts in the science of this particular developing field. In other words, scientists should taken it upon their personal mission to increase the public’s knowledge on and objectivity towards these kinds of matters.

A recent study examined perspectives of Millennials regarding GMOs, specifically GM foods[30]. Being a very large generational group, their perspectives are expected to have a major impact on acceptance of GMOs. Overall, Millennials have somewhat unfavorable views toward GM foods. In an attempt to understand that attitude toward synthetic biology, we made our own survey, which we distributed to a large public. It was answered by 381 persons, whom were mostly Millennials attending a university, from Canada or Europe. We asked respondents how they feel about GMOs and most of them seemed to feel safe about them, depending of the use that is made of them.



After that, we asked them a few more precise questions about GMOs on the market:
1. Would you trust a product synthesized by a genetically modified organism (GMO)?
2. Did you know that several products (cosmetics, food, drugs, etc.) are already produced by GMOs or are GMOs themselves?
3. If these products were labeled as GMOs, would you still buy them?
4. In your opinion, would it be necessary to specify the origin (chemical or biological) of adrenaline sold in pharmacies?
5. Considering that adrenaline is a drug and not a food product, does the fact that it comes from a GMO make it any different for you?


For each answer given to the previous question, we analysed the answers for the 5 following questions. Charts 1 to 3 (see appendix), which represent the majority of respondents (88%), show the same results: these people would trust a product synthesized by a GMO and if these products were labeled as GMOs, they would still buy them. In the same sense, they did not consider biologically synthesized drugs a different issue than GM food.

On the opposite, the respondents who answered that GMOs are harmful to health and the environment, charts 3 and 4, said they would not trust a product synthesized by a GMO and if these products were labeled as GMOs, they would not by them. Similarly they did consider biologically synthesized drugs a different issue than GM food, responding that drugs and pharmaceuticals were even riskier than food products.

In between, the rest of the respondents who had a neutral attitude towards GMOs, presented in chart 6, had a balanced position on those questions, saying that while they do not know if they would trust biologically synthesized adrenaline, most of them would buy products labeled as GMOs and they do not consider biologically synthesized drugs a different issue than GM food. The majority of all respondents considered it would be best to label GMO products and they already knew that several products are produced by GMOs or are GMOs themselves.

From the results of our survey, we can infer that those who do not consider GMOs as harmful also do not fear them. Considering that a majority of respondents in our survey are students who have a medium (37%) or high (44%) level of knowledge in biology, we can also suggest that those who are educated on that matter do not fear the resulting technologies of that field.

Another survey of public attitudes regarding synthetic biology found that nearly two-thirds of respondents supported continued development of the field, including additional research on its possible effects on humans and the environment[31]. There was a strong correlation between self-reported awareness of synthetic biology and support for ongoing research, as 80% of those who had heard a lot about the field believed it should move forward, compared to only 52% of those who had heard nothing about it. Overall, 73% of those surveyed reported having heard “just a little” or “nothing at all” about synthetic biology. These data indicate both the need for broader public engagement regarding synthetic biology and the positive impact of such efforts on public support for novel technologies.

In another vein, there are oppositions to synthetic biology that come from important areas of religions and ethics. Unlike the debate regarding human embryonic stem cell research, the Catholic Church does not oppose synthetic biology. Following the publication of a paper from the J. Craig Venter Institute, an official from the Catholic Church praised the development as “a further mark of man’s great intelligence, which is God’s gift enabling man to better know the created world and therefore to better order it.”[32] The statement encouraged continued synthetic biology research, provided that the research proceeded responsibly and did not undercut the sanctity of life.

Faith-based scientists also declared: “absolutely nothing accomplished in synthetic biology by way of synthesizing the genome of a self-replicating bacterial cell from its component parts - which is the most striking and specific technical achievement of the Venter Institute team - demonstrates that life is without mystery or value that goes beyond the assembly of its parts. The mystery of life is amply great, as both religious and secular minds can appreciate, to survive even the most masterful scientific feats[33]” . While religious thinkers suggested caution regarding the human tendency toward hubris, none expressed concern that synthetic biologists were “playing God”, which is an argument that can often arise in debates on this subject.[34]

Despite all that, we believe that there should be strict guidelines in place to regulate synthetic biology research, because responsible science should reject the technological imperative: the mere fact that something new can be done does not mean that it ought to be done. Conversely, how do we ensure regulations do not impede the progress of development? Three principles are prescribed to ensure that : the precautionary principle, the proactionary principle and the prudent vigilance. The first prescribes halting or substantially slowing the progress of scientific research until risks can be identified and mitigated. The second assumes that an emerging biotechnology should be considered “safe, economically desirable and intrinsically good unless and until shown to be otherwise”[35]. The last is a middle ground of those extremes, it prescribes to carefully monitor, identify, and mitigate potential harms over time.

In conclusion, biotechnology has the potential to affect everyone, and opportunities for the public to participate in discussion and deliberation about emerging technologies such as synthetic biology are critical. Robust public participation is essential in both the development and implementation of specific policies as well as in a broader, ongoing national conversation about science, technology, society, and values for the future.

Conclusion

Each team had an interesting experience doing this collaboration. We had the chance to exchange different points of view from our different countries and we managed to write a great report out of those discussions. Unfortunately, we barely covered three areas of the issues concerning synthetic biology, therefore there are still many other things we could still discuss about.

A word from each team concerning their experience on that collaboration: Toulouse-INSA-UPS: “We are so very lucky to have been able to collaborate all together on this subject. As we discussed above, the ethics behind biological research have become more important than ever, and in the context of our growing and changing world, we need to focus on just that: we are a part of the world, not just our country or our iGEM project. This humans practices-oriented collaboration has shown us all the diversity in this competition, and we hope that next year’s projects can unite even more different cultural backgrounds in a common goal.”

NUSGEM (Singapore Team-A): “NUSGEM is happy to have worked with Team Toulouse-INSA-IPS and Team ULaval on this piece about the bioethical, economic and cultural considerations of Synthetic Biology, its businesses and its technology. The human practices based research conducted by each of our teams has been instrumental in helping us understand the different facets of synthetic biology. Learning aside, this collaboration also served to illustrate how collaboration between different teams is important not merely a transactional relationship, but a synergistic one. We learned more than the sum of our individual sections combined, as we have gained a more holistic understanding of the field of synthetic biology.”

ULaval: “Here at Team ULaval we consider ourselves extremely lucky to have had the opportunity to work with Toulouse-INSA-UPS and NUSGEM Singapore iGEM teams. The collaborative work done on the human practices aspect of the project allowed us to look at synthetic biology with a new eye and with a different perspective. As synthetic biology is an ever-changing domain, we need to constantly re-evaluate how it affects society. We think that by working with teams from around the world allowed us to think more critically about the implications of our work. As a team that participates to IGEM for the first time, being able to work with veteran teams was invaluable. We look forward to meeting our collaborators in person!”

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igem@bcm.ulaval.ca