Responsible Research and Innovation

Bring innovation and societal needs closer

Connecting human practices closely to our project was our main goal and because we were working with the CRISPR-Cas9 technology, we tried to know more about it and to learn how to use it in a responsible way. Innovation often tries to answer a societal need. However, this societal need is not always reached for different reasons: because the innovation is not fit for the users, because it has deep negative impacts, because the project was not enough defined at the beginning ...etc. Sometimes the project even missed its goals, only because the desire to meet it was not followed by strong principles. Thus, in this project,bringing innovation and societal need closer animated us.

Our work to bring them closer was possible thanks to Responsible Research and Innovation principles. Responsible Research and Innovation is a nascent governance concept which aims to guide research towards societal goals. Those principles have been developed by the European Commission. Responsible Research and Innovation works as soft law: it is not meant to substitute to written law (hard law) but to complete it. Soft law like RRI has the advantage of quick adaptability, when written law is often late because it can't change as fast as science. Thus, we believe RRI is a good framework for the use of the CRISPR-Cas9 technology in our research, because written law did not already ruled on this brand new technology.

While working on the concept of Responsible Research and Innovation we had the idea to create a RRI Test, which works as a feed-back for the projects. The principles of Responsible Research and Innovation guided our research, and the RRI test helped us to reshape it to build a more responsible project. We thus integrated all our human practices on the CRISPR-Cas9 technology by the bias of responsibility and the RRI worked as a tool to integrate our human practices in our project. Indeed, this tool helped us to have a better decision making, more rational and guided towards societal needs. To see the RRI test, click here.

While we were already working on our project and RRI, we discovered that we followed the same idea as the European Union, which launched their RRI Toolkit this year, after two years working on it. This RRI Toolkit helps researchers to lead a responsible research by a wide range of tools. RRI is a strong idea that European Union tries to spread for 2020 for european researchers. Our test follows the same path for iGEM, an iGEM sized test.

We filled our test to see how we responded to the principles we wanted to follow. This test is divided in the four parts of RRI : Reflexivity, Anticipation, Inclusiveness/Deliberation, Responsiveness. We believe iGEM could be a great laboratory for these principles. Following this idea we share the test with several teams, most of them filled it and we tried to see how the four axes of RRI (Reflexivity, Anticipation, Inclusiveness, Responsiveness) are integrated by the teams.

The four axis of our reflexion on RRI:

• Reflexivity: The reflexivity leads the team to think about the choices that have been made, the motivation and potential impacts of the project. The question of reflexivity happens at the first step of the project. Reflexivity tries to find how the team thought about the purpose of the innovation.
• Anticipation: Anticipation requires to describe and analyze possible impacts, and create the appropriate solutions and policies. Every scientific project includes impacts. Even though all the impacts can’t be predictable at the beginning of the project, a lot of them can be seen. This anticipation is scientific but also juridical (decide about the best legal framework).
• Inclusiveness: Inclusiveness and deliberation require to listen to perspectives from publics and stakeholders. Inclusiveness requires to listen to stakeholders, but deals also with outreach and pluridisciplinarity.
• Responsiveness: Responsiveness is a good indicator for the efficiency of RRI in the project. It requires to search if the previous dimensions helped to shape the project toward the RRI’s goals.

What did we learn on our project?

Reflexivity

When we chose our project we had different options. We chose to take a fundamental project, risky bet but more original. Stakeholders were essential to help us build our project. They helped us to focus on many points and to put the project in perspective. We thus met many scientists, but also jurists and politicians. Was our project needed? We thought about the different applications of the project. It was not an easy task because the project is a fundamental one. We were guided by a publication of Olivier Espéli “From structure to function of bacterial chromosomes: evolutionary perspectives and ideas for new experiments”, which said a tool like ours would be useful for scientists (FEBS Letters, 2015). We find that our tool would be not only useful for biologists because of its simplicity, but also for the public health sector. This tool could indeed help to diagnose genetic diseases.

Defining the impacts of our project was complex as we choose a fundamental biology project. Even if we defined the potential applications of our project, other scientists or industrials can invent new ways to use our tool and guessing how they will use our tool is impossible. But the impacts of a responsible project cannot be only transferred to the user and his use in a environnemental or health context; science itself must be responsible.

With this reflexion came the main question the RRI test asked us: how RRI could apply to fundamental research, such as our project on the CRISPR-Cas9 technology? The societal goal does not seem to exist. However, building a responsible research is in itself a societal goal: having a more responsible science is undoubtedly a benefit for the society. The stakeholders of a fundamental project are the ones whose voices are interesting and necessary on science. In other words, the stakeholders are less identified. On our focus on the CRISPR/Cas9 technology we felt necessary to gather stakeholders and tried to draw with them the future of a responsible use on this technology.

Anticipation

The more we knew about the CRISPR-Cas9 technology, the more we realized we did not know much on this technology and its impacts. The difficult anticipation in the scientific field transferred our questions on the human practice. As a consequence, we try to learn from stakeholders what can be the burning issues on the CRISPR/Cas9 technology and to make CRISPR known to the public.

We believe anticipation can also be important in order to chose the right legal framework. Choosing an intellectual property scheme instead of another would have an important impact on innovation. So we asked ourselves what would be the right legal framework for fundamental biology according to the principles of Responsible Research and Innovation. As fundamental biology does not follow a specific societal need, a specific application, we could think patent would be a good option, because it would not harm public and stakeholders. On the other hand, if we consider science as a societal need itself an open license would be a better option.

Inclusiveness and Deliberation

We had a strong concern about inclusiveness due to our fundamental project. That is why we met a lot of stakeholders and public and in our case of fundamental research we defined the stakeholders as scientists using the CRISPR-Cas9 technology and Industrial Property Attorneys.

Popular Science: A Key Concern

As we believe popular science is a key concern in synthetic biology and especially for the CRISPR-Cas9 technology, we lead several activities in this field. During a vox pop, we saw that people were mostly unaware of synthetic biology itself. We thus tried to meet public, to discuss with us about synthetic biology, the CRISPR technology and our project.

We met students during an exposition in the Nanterre University, but also during the Festival Vivant, opened to everyone. What did we learn from this experiments? Most of the people we met trust scientists to be responsible in their use, and does not feel legitimate to bring a critic on a subject they do not master.

Conference: The Societal Issues of CRISPR-Cas9

Because we had a strong concern both on vulgarisation and meeting stakeholders, we hold a conference in our university, in front of students, with two researchers, Jean Denis Faure, a researcher and professor using the CRISPR-Cas9 technology on plants, and Pierre Walrafen a scientific with a cellular biochemistry and patent engineer.

We tried with our guests to think about the societal issues of the CRISPR-Cas9 technology, for the ethics, the law and the economy. The ethical problems the CRISPR-Cas9 technology is bringing are huge, and for most of them, unknown. The ethical problems come with what is done with the technology: therapeutical applications ex vivo or for genetical diseases, or applications on embryos and germ cells. The ethical problems come along with the question of transhumanism. The issues are rising because of the simplicity of the CRISPR-Cas9 technology, authorizing a wider scientific audience to edit the genome.

About the legal framework, our speakers made a comparison between the European legal framework, the process based evaluation, and the product based evaluation, and how the patentability was in Europe restrained by a principle of public order.

Meeting Stakeholders

Because we think meeting stakeholders is really important to build our project we met several of them.

As we said before, we met the professor Olivier Espéli, who helped us to shape our project. We also met Mr. David BIKARD, a reseacher at the Institut Pasteur in Paris and an expert on the CRISPR-Cas9 technology utilization. He helped us choosing which orthologous dCas9s to use for our project, in order to maintain the sgRNA/dCas9 recognition specificity.

On our Human Practices research, we met different stakeholders to think on this field. We met Agnès Ricroch is a professor at AgroParisTech school working on plants and their regulations, the professor Marc Fellous, Emeritus Professor at Paris Diderot University and Medical Doctor, Eric Enderlin a French and European Patent Attorney at Novagraaf, Geneviève Fioraso, french deputy and former minister of Higher Education and research, and Catherine Procaccia, French Senator working on a report on the economical and environnemental issues of new biotechnologies.

Those meetings helped us to define and shape our project, but also to think about the tool we were working on. We tried to meet stakeholders from the different fields involved (scientific, legal, politics), in order to have the broader view on the CRISPR-Cas9 technology.

iGEM Meet-Ups

We attend to two iGEM meet-ups, an European one, and an other, gathering the Parisian teams. We were part of the organisation of the Parisian meet-up.

These meet-ups helped us in two ways. First it was a great opportunity to have a feed-back from our peers. Then, we met there other teams working with the CRISPR-Cas9 technology which conducted us to collaborate with them.

Responsiveness

What did we learn?

On ethics:

Leading a project on fundamental biology involves to work a lot with stakeholders. In a RRI vision, a fundamental project is an opportunity to think about the responsability of science, in our case the CRISPR-Cas9 technology. We learned we should follow the principles of RRI to have the strongest connection between innovation and the societal needs.

The we saw that the potentiality of the CRISPR-Cas9 technology was huge. This leads to two things:

1. It’s very difficult to define precisely what could be the impacts, thus a harder work must be furnished on the subject;
2. Vulgarisation for the public is a key issue.

The CRISPR-Cas9 technology is easy to use, even by students and has big consequences. We should define the purposes with more rigor and strengthen the safety part.

Using the CRISPR-Cas9 technology requires to know about the gene before we can mutate its functions. This requires to work on genes we already know about or to have a strong research on the gene.

In the ethical field we should always balance the advantages and the disadvantage. Even if it seems obvious, it is fundamental to do this and to present the balance to the public opinion.

On law:

About the law on ethics the CRISPR/Cas9 technology challenges the traditional process-based law and results-based, because when you see the final results you cannot always say if it comes from a natural mutation or from an action of genome editing. About intellectual property we understood that to ways to think about patentability exists and are are strongly opposite. We have either to make a choice about how we see innovation or try to bring those two positions closer.

RRI Test: the answers of the iGEM teams

We asked iGEM teams to fill to our test. 18 teams answered to it, and thus helped us to see how the principles of RRI are respected in the iGEM competition. Their answers gave us new ideas to spread this principles, but also make us thought on how to improve the knowledge of this principles. Firstly, we saw that the RRI principles were not really known among iGEM teams: only 53% of the teams knew what it is.

Reflexivity

iGEM projects do meet societal goals. Most of them wants to address a major challenge of our time and solve it by synthetic biology. However, the definition of a societal need is very different from teams to teams.

The main question is: how to define a societal need? There is a lot of different projects, and a few ways to define the societal need the team wants to address: news report, questionnaire survey, meeting stakeholders, research in scientific papers. Other teams defined their project by their own knowledge but then meet stakeholders to build it.

Defining a societal need comes along with the question of the project itself: how did the team find the problem they want to address? Most of the teams looked around them: local problem of flu, Lascaux cave, problem of small and local research center, or major problems making the news, like Zika viruses or life on Mars, or just a desire to improve synthetic biology. A good example: iGEM Costa Rica decided to tackle prostate cancer because it is the second cause of mortality in their country.

In order to answer a societal need the teams need to identify to whom the project will apply, who will use it. Some teams like iGEM Istanbul Tech or iGEM Pasteur gives a really complete scenario of who will use it and how. Despite this teams, the users of the project are not always defined. The definition of the potential impacts is also a problem, because most of the team didn’t try to define it. We could think of a solution: we know Synenergene asks each year some teams to define a techno-moral scenario about their project. Techno-moral scenario could be spread in order to think about concrete applications. Moreover, an other work could be to think about a scenario of the worst application possible of the innovation. It would be a difficult but interesting exercise.

Anticipation

The answers of the test show the anticipation part is not well developed among iGEM teams. Most of the team admits they are waiting for the results to build an anticipation. This lack of anticipation is quite normal because the iGEM competition does not call projects to go beyond the competition. However, we think iGEM could play an important part for the spread of a principle of anticipation among researchers.

Teams which tried to anticipate want to make a new firm, in order to sell their new product. Other teams wants beyond iGEM to pursue the project by extending it to new fields (iGEM Manchester), or help other scientists (iGEM Istanbul Tech).

About the legal framework: If the bulk of the teams chose patent over open license for their project, most of them preferred a patent with humanitarian licensing than a traditional patent. It shows how teams wants to respond to societal needs. We believe iGEM could be a great laboratory for definition and test of legal frameworks. The legal framework is different for each project. This legal framework could be defined at the beginning of the project, in order to see what would be the best choice for the project to be economically interesting and meet societal goals. The anticipation of the framework could help the team to shape their projects and the goals they want them to reach.

Inclusiveness

Inclusiveness is one of the principles the most shared among iGEM teams. iGEM teams met as many stakeholders as there are projects. If we give a quick glance at it we can find among stakeholders: governmental agencies, farmers narcotic police officers and academicians, city hall, doctors, vets, European agency… Among this very different stakeholders, there is a lot of industry actors, showing that teams think how their project should be developed.. Sometimes there is a difficulty to meet industry actors in very specific fields (like space).

Because of the work of the iGEM competition on this field, popular science and outreach are well admitted and used among teams. Most of the teams lead actions of popular science among public or students. iGEM meet-ups are also important for inclusiveness. According to the answers they are often useful for the teams, they permit to increase the feasibility of the project. For example, a team discovered potential impacts while talking with iGEM teams at a meet-up.

In order to foster Inclusiveness the iGEM competition created in 2015 a special prize for Public Engagement. We believe it could be a good idea in the iGEM competition to have prize for Reflexivity and Anticipation (Responsiveness is already a price through the Integrated Human Practices).

Responsiveness

Teams had really interesting answers on how the different steps highlighted by the test helped them to reshape their projects, even if some teams have not seen their project reshaped. They found it useful to decide where they should direct the development of their project, and how to build feasible and long lasting project, positive for society. We could take the iGEM Valencia UPV as an example: after talking with farmers they understood their tool could not be used by farmers, and so aimed plant breeders. An other team realized they have to put more inclusiveness in their project.

iGEM Imperial members noticed how the principles changed the way they think about their project:

"Those processes shaped the way we now approach decision making during our project. They guide us through a logical, rational and societal process every time we pivot."

And the last words to the iGEM CGU Taïwan members, who summed it up in the best way possible:

"Reflexivity makes you a good start; inclusiveness makes you a good connection; anticipation makes you a good hope."

The question of evaluation?

Doing the test already provides a feed-back on the project. Should this feed-back be completed by an evaluation of the respect of the RRI principles? Such a tool would be useful to know where the team can improve. However the ways to respect RRI principles are diverse, and we saw teams can invent new ways to respect it every day. All of the criteria needed for an evaluation would never fit in a single evaluation, because the answers are so diverse, and new ways to address RRI principles can be invented by each team. We prefer to think the RRI Test as a helping tool for teams to think on their project, a feed-back in which they can have a look back on their choices and their compliance with RRI principles.

We would like to thank all the teams which filled the RRI Test!

Teams : iGEM XMU-China/ iGEM Manchester/ iGEM Toulouse/ iGEM Vanderbilt/ iGEM Valencia_UPV/ iGEM Istanbul_Tech/ iGEM UGent/ iGEM IONIS iGEM Pasteur/ iGEM Tec-Monterrey/ iGEM Imperial iGEM/ iGEM Macquarie Australia/ iGEM Sheffield/ iGEM Nagahama/ iGEM CGU_Taïwan/ iGEM Leiden/ iGEM Tec-Costa Rica.

References

Lagomarsino MC, Espéli O, Junier I. From structure to function of bacterial chromosomes: Evolutionary perspectives and ideas for new experiments. FEBS Letters. 7 oct 2015;589(20PartA):2996‑3004. http://dx.doi.org/10.1016/j.febslet.2015.07.002

König H,Dorado‐Morales P, Porcar M, Responsibility and intellectual property in synthetic biology, A proposal for using Responsible Research and Innovation as a basic framework for intellectual property decisions in synthetic biology, EMBO Reports, EMBO reports (2015) 16, 1055-1059. http://embor.embopress.org/content/16/9/1055

To learn more about the European Union project of RRI Tools : http://www.rri-tools.eu/en