In the Human Practices part of our project, we take a step beyond the lab and make sure that PHOCUS would do no harm. Also look at how we integrated Human Practices into our project. At the start of our project, we identified stakeholders relevant to our project and investigated their values, norms and needs, on which we based design requirements for PHOCUS.
To assess whether PHOCUS can really benefit the people and the environment, we have put a lot of effort into engaging many relevant stakeholders in the progress of our project. Our contact with stakeholders was handled with care. We tried to do this as ethically as possible according to the principles of ethical research by Vanclay et al. , which will be explained in more detail below. This contact was crucial for placing PHOCUS in the local context of parts of Africa and Asia. These environments are hardly familiar to our team and therefore, we put in extra efforts to identify their needs. For instance, we conducted a questionnaire among Kenyan and Indian farmers that were affected by locust swarms, we interviewed authorities (the FAO and a national ministry) on how they operate locust control, and had a discussion with locust control experts, governments and non-governmental organizations at the Virtual Practitioners Conference on Desert Locust Control Management 2020, where we presented a keynote lecture. Over the entire course of our project, the design requirements for PHOCUS changed by the input of many stakeholders, who gave us multiple rounds of feedback on the design of our biopesticide.
Not only the local social and economic context where we aimed to innovate was considered, also ethical, legal, biosafety and biosecurity factors were thoroughly investigated by talking to experts and other stakeholders. An elaborate overview of the biosafety design measures we deduced from these insights and literature can be found in Safety. Most importantly, our solution was designed to be safe to humans and the environment.
Finally, we considered any unintended effects of PHOCUS. We learned that, from a safety risk perspective, our project is a very interesting one to study. Our project inspired Andrea van Langen to write her Bachelor Thesis at the TU Delft Biotechnology & Society group about responsibility and safe-by-design considerations of PHOCUS. Also, PHOCUS is proposed as a case study that eventually could be used by partner organizations, of which i.a. the Dutch Ministry of Infrastructure and Water Management. Within the team, we also discussed our responsibilities and risks involving our project with the guidance of the iGEMers Guide to the Future. From this discussion, we learned that we as a team may hold different perspectives of the notion of responsibility, but we should always do our best to mitigate risks and prevent unintended usage.
Important to us, and the iGEM competition in general, is that the technology and ideas we develop aid in the improvement of society, by solving a large societal problem. It is paramount to consider how a project can impact society with a broader view than just solving the identified problem. By participating in Responsible Research and Innovation, the goal of innovation shifts from "science in society" to "science for society" . It is vital to identify different groups of people, who will be affected by or have influence on your project, these groups are called "stakeholders". Stakeholders have different values, norms and needs that could clash and need to be taken into account during the design of our project. Overcoming these differences is challenging, but could lead to a more complete solution to the problem that is beneficial to society. On top of that, it is key to recognize that our own values are embedded in the technologies we develop, which opens up our project to prejudice among other things .
The transfer of our project from our personal perspectives to that of the stakeholders was done through ensuring that their values and norms are incorporated into a Value-Sensitive Design. First, the key stakeholders were identified. These stakeholders were positioned on a power-interest grid, which is a visual tool that aids in understanding the implications of the power and influence of stakeholders on our project . From this, we identified appropriate communication strategies and prioritized the values and needs of powerful stakeholders with a lot of interest in our project. Second, interviews with the key stakeholders were conducted to obtain an understanding of their values and norms. Specifically, the purpose of these interviews was to gain insights in the stakeholders’ perceptions of the problem and the current and desired solution. The different values and their associated norms of the stakeholders not only gave us insight into what each individual finds important, but also provided an overview of the collective. This helped to identify potential clashes between values and indicated which values should form the core of our technology. These values were, in turn, translated into design and operation requirements. Due to the size of our analysis, we only show an example here. Figure 1 depicts how the value “food safety” has been translated to a norm and design requirements. A norm depicts how we interpret the value as a sort of rule, e.g. for something to be safe, food needs to have no or little hazardous compounds on or in it. From thereon, specific design requirements can be derived as to how to uphold the norm. There are multiple ways as to achieve this, hence multiple design requirements can be derived.
After identifying the values and norms of stakeholders and deducing design requirements, clashes between these were determined. As an illustration, one of the main clashes that was identified is the clash between the values “environmental safety” and “food security” in choosing between a lytic or lysogenic bacteriophage. A lysogenic phage does not spread as fast as a lytic phage and therefore, may be considered to be more environmentally safe. On the other hand, the fast spread of such a phage in the gut microbiome may result in the production of higher toxin concentrations, which benefits food security. However, a lysogenic phage integrates into the bacterial genome, which allows for horizontal or vertical gene transfer, which may have unintended side-effects. Thus, a lysogenic phage may be less environmentally safe than a lytic phage. Ultimately, we decided on a lytic phage.
A stakeholder value matrix was used to establish to what extent our design iterations were in accordance with the stakeholders’ values and was used as a tool to monitor our progress towards meeting as much of the values as possible. Whether design iterations complied with the values of the stakeholders was repeatedly tested through feedback loops of stakeholder interaction.
A potential pitfall for scientists and engineers is to be too focused on their invention being the only solution to a problem, they do not take into account potential environmental influences. Moreover, they may not consider that their potential adopters may have different perceptions of the problem and the desired solution. By improper communication about the perspectives of stakeholders, scientists and engineers may not take into account the context they are inventing for. This could mean that the implementation of this solution will not have the impact its inventors aspired it to have.
We acknowledge that, to make a societal impact with our innovation, we have to be aware of who our stakeholders are, what they value, and keep them involved in our project. Therefore, from the start of our project, we placed great emphasis on approaching, engaging and analysing stakeholders in the appropriate way. Here, we describe our process of identifying and managing our stakeholders.
Identification of stakeholders
By identifying groups who have an interest in solving the locust crisis or in our project itself, we have identified and engaged stakeholders who may play a role in developing and implementing PHOCUS in the real world (Figure 2).
- Farmers in affected areas are the ones that would benefit the most from the implementation of Phocus, as these people suffer from crop losses and are exposed to harmful chemical pesticides. Hence, the integration of their values and perceptions into our project have high priority.
- The end-users of Phocus are the people and organizations that are currently responsible for locust control management:
- The Food and Agriculture Organisation (FAO) of the United Nations is responsible for global locust control. It aids national governments financially and operationally in their locust control efforts.
- National governments of affected areas are responsible for national locust control efforts. In practice, they are highly dependent on the FAO.
- The end-users are also regulators, such as national governments, and therefore, play a key role in acquiring admission for Phocus to be applied.
- The public at large has to be generally accepting of using genetically modified bacteriophages in their country. This includes civil society organisations, such as environmental organisations.
- Companies in the agrochemical industry may support our project through providing us information or funding, or, in case they feel threatened by upcoming competition, form hurdles against us through lobbying.
- It is important to engage the scientific community in our project to obtain technical feedback on our project.
Reaching out to stakeholders and establishing feedback loops
We approached our stakeholders through email. In this email, we introduced ourselves, our project and why we are interested in approaching that particular stakeholder. Also, we asked whether they would be interested in sharing their insights in an interview. Unfortunately, due to the COVID-19 pandemic, these interviews had to be held online. However, meeting online lowered the threshold to meeting with people worldwide, it allowed us to reach out to stakeholders not only in the Netherlands, but also, for example, in Africa and North-America.
In general, we tried to adhere to principles of ethical research by Vanclay et al. , for instance, informing interviewees about our intentions, not giving them hope that PHOCUS will actually be implemented anytime soon, ensuring their voluntary participation, communicating the results and allowing them to change these, and asking for permission to share any of the results on the Wiki.
Before the interview, we prepared questions and sent these to the interviewee in advance. At the start of the interview, we introduced ourselves, our role in the team, and our project to the interviewee through a presentation. In addition, we asked for informed consent to share our insights from this interview, including the name and photograph of the interviewee, on our Wiki page and whether it was okay if we would make a transcript. After the presentation, we performed a semi-structured interview using the questions that we sent. Once the interview was finished, we summarized the key points from the interview and sent it to the interviewee for additional permission to publish the exact words. In some cases, we introduced our project idea in a later stage of the interview as not to influence their description of the problem.
Every two months, we sent the stakeholders that we talked to up to that point an email, in which we communicated the progression of our project and the way in which their interview impacted our project, to keep them engaged. Sometimes, this yielded interesting replies that also resulted in an adjustment of our project.
The following chapter will explain with whom and how we have had contact throughout the project.
- End-users: We had continuous contact with two locust control experts, Dr. Mamoon AlSarai Alalawi and Prof. Alexandre Latchininsky, from the FAO throughout the project, both via video calls and emails. They taught us locust control is only performed by professionals. In addition, we have had online meetings with two locust control experts who used to work for the FAO for many years: Em. Prof. Arnold van Huis and Harold van der Valk. We presented our initial plan to them, which was to stop the swarming behavior of the gregarious locusts. When both of them advised us not to do this because this strategy may do more harm than good, and to kill the locusts instead, we changed our entire project. We also had continuous contact through video calls and emails with Susan Nguku, Agriculture Extension Officer of the Kenyan Ministry of Agriculture. Susan is a representative of the national government of Kenya, which is one of the countries that is most affected by locust swarms. She told us about how scared people got when locust swarms arrived.
- Farmers in affected areas: Affected farmers were very difficult to reach out to. We tried to establish contact with multiple farmer organisations in parts of Africa, but with no success. Ideally, we would have gone to one of the affected regions, but unfortunately, travel restrictions due to COVID-19 did not allow us to go there. Luckily, Susan Nguku, from the Kenyan Ministry of Agriculture, works very closely with farmers that have been affected by locust swarms and was able to articulate their experiences to us. In addition, she helped us in reaching out to farmers through conducting our questionnaire with Kenyan farmers. We also got in contact with farmers from India through our contact person, Shanu. Although both countries suffer from the same problem, we were wondering if there were any differences in how they perceive the problem and solution.
- Regulators: The use and release of genetically modified material is under strict regulation. We reached out to Cécile van der Vlugt, a senior risk assessor from the Dutch National Institute for Public Health and the Environment. She is specialized in risks associated with GMOs. We discussed and assessed different types of risks associated with PHOCUS. Our lack of additional biocontainment strategy should not pose a problem if we can prove our claim that it will not propagate in nature.
- Public at large: We reached out to many environmental organizations, such as Greenpeace, Friends of the Earth, ETC group and Milieudefensie. Unfortunately, none of them wanted to discuss the impact of chemical pesticides on the environment or their perception of PHOCUS with us.
- Companies in the agrochemical industry: Companies in the agrochemical industry: We reached out to many agrochemical companies, both small and large, to raise awareness of the biopesticide we were developing, to obtain feedback on PHOCUS and to see whether we could help each other in any other way. We had a meeting at our faculty in Delft with Remco and Gerard Bod from Simonis BV, which is a Dutch insecticide and pesticide exporter and one of the official suppliers of the FAO. They elaborated on the approval process of new pesticides. They were enthusiastic about our project and even showed great interest in making an investment. After our meeting, we kept email contact.
- Other people from the industry we have had contact with include dr. Frank van Steenbergen from MetaMeta, a company involved in bottom-up locust control, and dr. Steven Hagens from MICREOS, a company involved in improving food safety and quality using bacteriophages. After talking to dr. Frank van Steenbergen, we even got invited to present a keynote lecture about our biopesticide at the Virtual Practitioners’ Conference on Locust Management 2020. This conference was also attended by representatives of a.o. FAO, Oxfam Novib UK, International Centre for Insect Physiology and Ecology, Pakistan Ministry of National Food Security & Research, Kenyan Ministry of Agriculture, University of Bath, Penn State University, University of Graz, Arizona University. Speaking at this conference provided us with the great opportunity to talk to locust control experts and scientists from all over the globe. This would have never happened if we did not repeatedly keep dr. Frank van Steenbergen involved in our project. From this, we learned about the state of locust control by the FAO and the national governments of India, Pakistan and Kenya, and about the newest scientific accomplishments in this field. Current trends in locust control include a.o. community-based surveillance and satellite-based monitoring of developing locust swarms. From a talk by Mohammed Khurshid from the Pakistan Ministry of National Food Security Research, we learned that locusts are a very nutritious source of food. This inspired us to investigate the idea of using dead locusts as a sustainable food source. This idea is elaborated upon further in the Integrated Human Practices section.
- During the course of our project, multiple researchers from the scientific community were of great help for us regarding the technical details, and safety, security and ethical considerations. For instance, based on advice from Em. Prof. Arnold van Huis and Harold van der Valk, we stopped our initial plan of stopping the swarming behavior of locusts and took on the strategy of killing the locusts. From Harold van der Valk, we were taught that Bacillus thuringiensis (Bt) toxins generally do not pose safety concerns to humans or the environment, which made the use of the locust-specific Bt toxin Cry7Ca1 a potential candidate for killing locusts. From Prof. Jozef Vanden Broeck we learned that desert locusts have a strong response to RNA interference (RNAi). This can be used as an effective way of halting essential gene functions, thereby killing the locusts. Therefore, we pursued this strategy. From Omer Lavy, we learned that the composition of the locust gut microbiome is not stable over time. Therefore, we decided to use a cocktail of engineered phages to infect the bacteria that are most prevalent in the desert locust gut according to his metagenomic data.
The field of research in which the scientists we talked to work include:
- Bacteriophage biology: Dr. Franklin Nobrega and Dr. Steven Hagens
- Plant pathology: Prof. Jeffrey B. Jones
- (Tropical) Entomology: Prof. Jozef Vanden Broeck and Em. prof. Arnold van Huis
- Insect physiology and ecology: Prof. Baldwyn Torto
- Locust population dynamics: Dr. Cyril Piou
- Toxicology: Harold van der Valk
- Microbiology (locust gut microbiome): Omer Lavy
- Biosafety and biosecurity: Dr. Piers Millet
- Bioethics: Dr. Zoë Robaey
Responsibility and risks
When designing and constructing a novel technology, it is important to be conscious about the risks and responsibilities that this brings about. Our project revealed to be a very interesting case for studying responsibility and safe-by-design. It inspired Andrea van Langen to use PHOCUS as a case study for her entire Bachelor Thesis at the TU Delft Biotechnology & Society group, titled “Bacteriophages as agents against locust swarms: A Safe-by-Design study on the application of gene and microbiome therapies” . In addition, the PHOCUS project is proposed to be used as a case study for a workshop which is currently being developed by a PhD researcher at TU Delft. The goal of this workshop is for participants to gain insight in what values are associated with potential risks, and how to identify ‘new’ risks. Eventually, this workshop could be used by, amongst others, the Dutch Ministry of Infrastructure and Water Management (IenW).
To prevent unintended consequences of PHOCUS, we tried to think of as many bad effects as possible. The most relevant bad effects from this list were discussed within our team and with biosecurity expert Dr. Piers Millet. For the discussion within our team, we made use of instructions of the SynBio conversation tool from the iGEMers Guide to the Future. On posters we wrote down five different provocative statements or scenarios involving risks of our project and the notion of responsibility. On the top, our team had to write down the possible causes using post-its and at the bottom, the possible consequences. Afterwards, the findings were discussed in the group, from which we drew conclusions. The statements or scenarios, including their possible causes and consequences and the conclusions we drew from the discussion, are stated below.
"Malicious use of PHOCUS is our responsibility"
We feel like the benevolent use of PHOCUS is our responsibility as we are, to a certain extent, able to anticipate potential uses. Also, as engineers we hold the responsibility to limit the extent to which PHOCUS is prone to malicious use. However it is difficult to foresee everything, but it is our responsibility to anticipate most. As a consequence of our responsibility, we make it as safe as possible, which is an upside of this sense. However, it also hampers technological advancement when there is a fear of dual use potential, which can be both good and bad. This is because together with responsibility may come accountability. In conclusion, we should do our best at making PHOCUS as inherently safe as possible, but we are also aware that not everything can be reasonably prevented and safety can never be guaranteed and therefore we cannot be responsible for everything PHOCUS is used for.
"PHOCUS has become an uncontrollable and mutated virus"
PHOCUS may become uncontrollable when it would spread everywhere and persist in nature. Would we have the tools and resources to monitor it or to stop it? We discussed that no kill-switches have ever been designed for phages, meaning we cannot just kill the phage in a particular condition to prevent it from spreading. We came to the conclusion that due to competition with wild-type phages for host infection, together with reduced fitness, PHOCUS will not persist in nature. Also, PHOCUS kills its hosts, which decreases its own chances of replication, a form of self-limitation. This means that PHOCUS becoming uncontrollable is improbable, but still should remain at the back of our minds throughout the development.
We also discussed what could happen if PHOCUS becomes mutated. A chance exists that a random mutation in the phage genome occurs. However, for this mutation to form a problem, it must be one that leads to pathogenicity of the phage or the production of a compound that is harmful for anything other than the desert locust. Furthermore, for this mutation to persist in nature and take over the population, it would be one that has a competitive advantage. Thus, we feel this is improbable, but still not impossible and should not be forgotten.
"Overzealous use of PHOCUS has eradicated the desert locust"
The overzealous spraying of PHOCUS could be caused by a lack of communication between countries and insufficient training of the people who would apply PHOCUS. The eradication of the desert locust could lead to an imbalance in the ecosystem, since it is part of a food chain. The exact consequence is difficult to predict. However, we seriously doubt whether this could ever lead to the distinction of the desert locust. Still, we turned to locust population dynamics expert Dr. Cyril Piou for advice.
"PHOCUS is harmful for (human) health and environment"
We already thought extensively about whether the phage, the Cry7Ca1 toxin or shRNA for RNA interference could be bad for (human) health and the environment. Using this statement, we wanted to investigate whether any unforeseen risks exist.
PHOCUS could be harmful for the environment if the phages that are sprayed on the plant kill all of the bacteria, and if this would affect the wellbeing of the plant or animals or hamper the role bacteria play in nutrient cycling. However, the chances that this happens are small, because we aim to place a physical barrier between the phage and bacteria when the phage is not in the locust gut.
Another way in which PHOCUS can be bad for people or animals is when the phage mutates in a way that the toxins become toxic for other beings than locusts. We decided to talk about this issue with phage expert Dr. Steven Hagens.
Another issue we have considered is what would happen if, for instance, a bee would ingest PHOCUS. Would this kill the bacteria in its gut? And if the bee has a symbiotic relationship with its bacteria, would this affect its wellbeing? We came to the conclusion that, similar to humans, these symbiotic bacteria probably maintain in the gut through a sort of mucus layer formation, meaning that the chance that all of it will get killed by phage infection is small. Still, we should be careful in determining a target bacterium and should do appropriate safety testing before release.
The consequences of this scenario occurring could be detrimental: it may lead to serious injury, loss of biodiversity, trigger phage resistance, and reduce crop variability. Moreover, people would blame us and biopesticide may get a bad reputation and therefore, may not be used anymore.
"PHOCUS can be used as a bioweapon"
It was discussed that theoretically, a phage can be engineered to make a bacterium produce anything. As bacteria are everywhere, this would allow you to produce anything anywhere. We decided to reach out to biosecurity expert Dr. Piers Millet to help us to assess this risk.
From the first discussion point, we obtained awareness of the fact that we all have different perceptions of responsibility. Still, we all find it important to do our best at ensuring that risks involved with PHOCUS are minimized.
Even though we think that PHOCUS becoming a mutated virus is not probable, we decided to ask phage expert Dr. Steven Hagens what the chances are to be sure. Dr. Hagens agreed with our thoughts on the chances of PHOCUS becoming mutated. In addition, he told us that the phage genome has evolved for millions of years to get to the optimal state where it is at, and therefore, generally any mutation will reduce the phage’s fitness. This means that this will not lead to a competitive advantage and will not sustain in nature. Based on this statement, it could be said that the chances of PHOCUS becoming mutated in a way that would be harmful for humans and other animals is negligible.
Based on our discussion of the third scenario, in which overzealous use of PHOCUS has eradicated the desert locust, we asked locust dynamics expert Dr. Cyril Piou whether this is possible. He assured us that there will always be some solitary locusts somewhere minding their own business, hence, our method does not risk eradicating the locust species.
The discussion of PHOCUS being potentially used as a bioweapon motivated us to talk to biosecurity expert Dr. Piers Millet. From our discussion with Dr. Millet, we learned that biosecurity issues arise from platform technologies. Therefore, we decided not to advocate nor explore the potential of PHOCUS being used as a platform technology, but instead, maintain focus on its niche application, which is killing locusts.
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