Team:TU Eindhoven/Human Practices

Human Practices

• Integrated human practices


• Stakeholders


• General practitioners


• Responsible Research & Innovation

Integrated human practices

Choosing our project

When choosing a direction for our project, we decided that we wanted to fight a worldwide problem. One problem that we came across and found particularly interesting was the ever-increasing problem of antimicrobial resistance (AMR). When researching this topic further, we came across the use of bacteriophages for therapy in some parts of the world. After talking to our supervisors, we concluded that a project on therapy would be a bit too ambitious in our limited period of time. Diagnosis, however, would be a viable option. This gave us the idea that the specificity of bacteriophages could also be used for the detection of bacterial infections, instead of treatment for bacterial infections as is done with phage therapy. Using bacteriophages would be beneficial compared to current methods. Automatic and fast amplification of bacteriophages takes place, after which an increase in bacteriophage DNA can be measured using a dCas9 system that is coupled to a bioluminescent protein. The bioluminescent signal that is produced will indicate whether certain bacteria are present.

Background information

The background information on bacterial infections and a confirmation of the necessity for the improvement of the detection of these infections came from Prof. dr. Chris Arts, who works with infections concerning prosthetics. While figuring out how to execute this plan, we found that there was almost no knowledge about bacteriophages at our university, so we looked around for experts in this field. Dr. Jean-Paul Pirnay, from the Queen Astrid Military Hospital in Brussels, works with bacteriophages and was willing to help us out. We even got the offer to do parts of our experiments in his laboratory, am offer we could not refuse! He also pointed out that it would be more clinically relevant to detect dsDNA than ssDNA, which resulted in the design of our detection method. Another tip we got was to add a heat step to our system to denature the bacteriophages, so we would be able to detect enough phage DNA. Luckily for us, there is an abundance of knowledge about CRISPR Cas and bioluminescent proteins at our university and in academic articles, so most of our questions on those subjects were quite easily answered.

Designing a prototype

Through a student contest at our university, we got to know Medtronic, a company focused on medical technology. While talking with their representatives, we realized that it is important to think about what part of our project can be shown to our stakeholders to make it clear what we are working towards. This is when we came up with the idea to design a prototype of a point-of-care detection system that incorporates our technique. A device like that could be useful for general practitioners, so they can better help their patients by giving them a more specific and correct treatment. Therefore, we also talked with a few general practitioners, to find out what they think about our idea. Most of them thought that our device would be really helpful for them and their patients.

Improve on current methods

For our detection system to be successful, it needs to be better than the currently available methods. We wanted to achieve this by making it faster, more specific, and more modular, and therefore easier to use, than the current methods. In conversations with stakeholders, we found out that time is the most important factor for improvement. The other two factors always need to be sufficient as well. For more information about current procedures for bacterial detection, we contacted PAMM, an independent laboratory that takes care of microbiological diagnostics. We also got some information about an old detection method for bacteria with the use of bacteriophages from a biosafety officer at the RIVM who had previously worked for Fabagen (Phage bacteria genetics), where she worked on this subject.

To further explore the current detection methods for bacterial infections, we contacted Dr. Stijn Konings and Dr. Heidi Ammerlaan who are internist-nephrologist and internist-infectiologist and were able to tell us about procedures concerning bacterial infections. Being able to faster distinguish between dangerous and less dangerous would be a major improvement in diagnostics. From these conversations, and another meeting with PAMM, where we joined a pathologist in the lab for a few hours, we got more information about the current status of the development of AMR. This included a website where you can very nicely see the proportion of resistant bacteria for certain antibiotics within Europe (Figure 1). From this website and the information from our stakeholders we could conclude that multi-resistant bacteria are becoming more and more of a threat to human health.

Figure 1: The occurrence of resistant bacteria in 2017 in Europe, 1A: Staphylococcus aureus in combination with Meticillin (MRSA), 1B: E. coli in combination with Aminopenicillins, 1C: E. coli in combination with Aminoglycosides, 1D: E. coli in combination with Carbapenems.

Animal health care & the food industry

Next to finding out everything we could for human healthcare, we were also interested in the proceedings in the animal health care and the occurrence of bacteria in the food industry. For this reason, we contacted GD Animal Health, a company that carries out lab work and helps companies monitor their animal health. From them, we heard that, while a lot of sources might suggest otherwise, it has been proven that there is no correlation between the development of AMR in animals and humans. We were also told that the most interesting part of our project, to GD Animal Health, is the part of the DNA detection, because it could be used in other applications as well. At Den Eelder, a dairy farming and dairy company, we heard the same about there not being a correlation between AMR in animals and humans. This company also told us that faster detection of their cattle’s infections would result in faster and more specific treatment of their cattle, which would mean that the milk can be used earlier for production again. This dairy company doesn’t see the use of bacteriophages as an alternative to antibiotics as a viable option, because they think it might interfere with the production of buttermilk for example, in which bacteria are used. It might however still be an option when specific phages for the infection are used, as these would not interfere with the useful bacteria in the production process.

Ethics

We also looked at our project from an ethics perspective with Dr. Lily Frank. Here we mostly talked about the impact that a point-of-care device like ours would have on the world. What we learned from this was that our device would be easy to use, benefit patients, and reduce healthcare costs.

Follow-ups

After each meeting with a stakeholder, we wrote down the most important conclusions and the follow-up that concluded from a meeting. These follow-ups were thoughts that we had after a meeting, however, not all of these were actually carried out. After discussing these thoughts with the team, some follow-ups seemed not necessary, or were too difficult or too time consuming to carry out.

Stakeholders

During the project we talked to different stakeholders to gain insight into how best to shape our project. On this page you can read about all our conversations and interactions with our stakeholders, and how they affected our work. For information about our contacts with general practitioners, click here.

March 12, 2019 - Meeting with supervisors

In a meeting with our supervisors, we discussed several potential projects. They mentioned that antimicrobial resistance (AMR) is an interesting problem and that there are several angles that can be used to deal with this problem.

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March 12, 2019 - Meeting with supervisors

In a meeting with our supervisors, we discussed several potential projects. They mentioned that antimicrobial resistance (AMR) is an interesting problem and that there are several angles that can be used to deal with this problem. Because of the worldwide relevance of the problem, there are many opportunities for Human Practices with this problem as well as sponsor opportunities, if we would be able to come up with potential solutions. The use of bacteriophages would be very interesting, but the supervisors told us that a project on therapy would be a bit too ambitious within our period of time. A project on diagnosis, however, would be a viable option and improvements in diagnostics of bacterial infections could play a crucial role in reducing AMR.

Most important conclusions:

• Focus project on diagnosis instead of therapy within the problem of AMR.

April 15, 2019 - Prof.dr. Chris Arts

We contacted Chris Arts to get some feedback on our ideas from an expert in the field of implant surgery. He helped us to think about who our target audience is and could be in the future.

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April 15, 2019 - Prof.dr. Chris Arts

Chris Arts is Associate Professor of Translational Biomaterials at the TU/e research group Orthopedic Biomechanics and at the Maastricht University Medical Center where he heads the Laboratory for Experimental Orthopedics. One of his research fields is the treatment of infections, which is why we contacted him to discuss our idea for this project. While our project initially focused mainly on urinary tract infections, Chris Arts is an expert in the field of infections that occur around prosthetics.

Currently, when a possible infection is seen around a prosthetic, it takes at least 4.5 hours before any result about the nature of the infection can be obtained. The complete surgery that takes place in these cases lasts shorter than these 4.5 hours, so the results are not available in time before the surgery ends, and they cannot be used for specific treatment. A faster detection method will therefore be important in these situations, because the results might change the procedure during surgery. This can mean that in some cases less follow-up surgeries are necessary or that the implant does not have to be removed at all, which saves a lot of money and provides a more comfortable overall treatment for the patient. For such decisions, it is important that there will not be any false negatives, because this will endanger the patient even more than a slow detection. So, the detection method shouldn’t be too specific for fear of missing an infection.

An issue with the detection of bacteria around prosthetics is the formation of a biofilm. This is an impenetrable film that cannot be seen by the naked eye and makes it impossible to detect any of the bacteria that are inside it. Because of these biofilms, possible infections around prosthetics are always treated with a broad range of antibiotics, just to be sure that all the bacteria that might be present will be attacked. The only way to detect bacteria inside a biofilm is by breaking it open. For now, our detection method will therefore be unable to detect these bacteria.

Another possible application that Chris Arts mentioned for our detection method is the screening for the MRSA bacteria in foreigners who come to Dutch hospitals for treatments. The MRSA bacteria are a group of common bacteria that are not a large-scale problem in the Netherlands, but that are more prevalent in a lot of other countries. There are no antibiotics available for these bacteria anymore, so the spread of these bacteria within a hospital should be avoided. This is done by putting patients with a possible infection in quarantine as a precaution. A fast detection of these bacteria will ensure that only patients that actually carry the infection have to be put in quarantine.

Most important conclusions:

• Fast detection of infections might affect decisions during surgical removal of prosthetics.
• False negatives endanger patients, so avoiding these is prioritized over fast detection.
• With current methods, biofilm formation on prosthetics hinders detection of bacteria types.
• Fast detection can be used for the screening of possible infections with MRSA bacteria.

Follow-up:

• Fast detection is very important, so we try to incorporate that in our project.

May 22, 2019 - Netherlands Biotechnology Congress (NBC)

The Netherlands Biotechnology Conference is a yearly organized event in the Netherlands where experts, companies and researchers gather to talk about the latest developments within the field.

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May 22, 2019 - Netherlands Biotechnology Congress (NBC)

The Netherlands Biotechnology Conference is a yearly organized event in the Netherlands where experts, companies and researchers gather to talk about the latest developments within the field. Most Dutch iGEM teams presented a poster about their research and it was the first time to hear about the projects they were working on. Phage-expert Dr. Stan Brouns held a presentation on CRISPR-Cas systems and provided us with new knowledge about other Cas proteins than the Cas9 protein that we are working with. Furthermore, PhD-student Britte Bouchaut spoke about her research on Safe-by-Design within biotechnology. Also, we discussed the problem of antimicrobial resistance with the iGEM Leiden 2018 team who also focussed on this problem in their project last year.

Follow-up:

• Investigate options of using other Cas proteins.
• Incorporate Safe-by-Design in our project.

Figure 1: Jeroen Deckers and Harm van der Veer at NBC.

May 28, 2019 - Dr. Jean-Paul Pirnay

We discussed the progress of our project with Jean-Paul Pirnay, an expert on bacteriophages, and got important feedback on our plans regarding the phage types to use, and how to get our detection system to work.

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May 28, 2019 - Dr. Jean-Paul Pirnay

Jean-Paul Pirnay is an expert in the field of phage therapy. He currently works in the Queen Astrid Military Hospital in Brussels, where he does research in the Laboratory for Molecular and Cellular Technology. We contacted him because of his expertise in the field of phage therapy. Daniel de Vos was also present in the meeting. He works in the same laboratory and has a lot of experience with phages.

In Belgium, in contrast to the Netherlands, phage therapy is already available. In the Queen Astrid Military Hospital, research on phages is being performed to improve phage therapy. It is still difficult to quickly determine which phage should be used for phage therapy. In bacterial infections, often multiple bacterial strains are present and it is desired to target them all. Therefore, our detection method to quickly determine which phage(s) is/are needed is relevant for the development of improved phage therapy. This would also be compatible with other iGEM projects.

Furthermore, Pirnay & de Vos pointed out that the PhiX174 phage we would like to use is not clinically relevant for phage therapy. For phage therapy, only dsDNA phages are used. Therefore, we decided to switch to dsDNA phages for the proof-of-concept to make it more relevant.

Our initial idea was to detect free DNA that is not packed into the daughter phages. However, it is unknown whether there will be enough free DNA to detect and the amount of free DNA will most likely be different for every phage. Therefore, they suggested that we detect the phage DNA that is present in the daughter phages, so enough DNA is present for detection.

Finally, we got some useful information about phage therapy in general. The Eliava Institute in Georgia has been using phage therapy for years already, but in Western Europe it is not used. This is due to a difference in legislation between these countries. In the Eliava Institute they work with phage cocktails that contain unknown concentrations of different phages. Due to legislation, this is not possible in the Netherlands. In Belgium an exception rule is managed, enabling the use of phage therapy.

Most important conclusions:

• Determining which phages to use for patient-specific therapy is laborious.
• There is uncertainty if enough free phage DNA will become available for detection.
• Difference in legislation between Georgia and Western Europe is the main reason for not being able to use phage cocktails here.

Follow-up:

• Focus more on the application of phage therapy instead of for antimicrobial therapy.
• We will only work with dsDNA (not ssDNA) for a more clinically realistic proof-of-concept.
• To increase the detection limit, we will investigate an additional step to also be able to free and detect packed phage DNA.

Figure 2: Harm van der Veer, Anouk Marinus, Eva Hanckmann and Claire Michielsen with Dr. Jean-Paul Pirnay at QAMH.

June 5, 2019 - Kilian Vogele

Last year, Munich’s iGEM team worked on their Phactory approach to produce phages for therapy using a cell free production method. This project continued after iGEM 2018, and while Kilian and Nino were working on this in Brussels, they had some time to meet with us to talk about what they were up to and how they might be able to help us out with our project.

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June 5, 2019 - Kilian Vogele

Last year, Munich’s iGEM team worked on their Phactory approach to produce phages for therapy using a cell free production method. This project continued after iGEM, and while Kilian and Nino were working on this in Brussels, they had some time to meet with us to talk about what they were up to and how they might be able to help us out with our project.

Kilian knew about some interesting papers that were published just this year about antimicrobial resistance (AMR). The numbers in these papers indicate that the AMR problem grew by 30% over 8 years for MRSA, but the problems are even bigger for resistant E. coli, with a growth of 400% over 8 years.

Previously, when we talked to Jean-Paul Pirnay at the Queen Astrid Military Hospital in Brussels, we were wondering about the possibility of detecting free phage DNA after lysis. Here Nino agreed with Jean-Paul that it is really phage type dependent and the free DNA is probably not amplified that much. There was also agreement about the burst size of phages, which is dependent on phage type, bacteria and the environment. Kilian said the burst size of the T7 phage is about 200-300.

Kilian expressed some concerns about the K_d of the dCas9 for the target DNA, as it would probably not be in the femtomolar range, where the [DNA] would probably be in. He suggested modelling this with some simple ODE’s (ordinary differential equations) in Matlab. If the phage-based amplification alone would turn out not to be enough, we could implement isothermal amplification method, like iGEM Peking 2015 also did, as suggested by Kilian.

Kilian also mentioned the recent sherlock Cas12 method which might be an alternative for our dCas9, as it has an inherent great amplification approach.

When asked about whether they saw potential in our method for advancing phage therapy and/or specific administration of antibiotics, Kilian said that a selling point of our method compared to the conventional methods could be that our approach can be applied directly to a patient sample to generate a phagogram and bacteriogram without isolation of one specific bacteria type first. Nino agreed with this.

According to Kilian, France and the Netherlands are working on a similar framework as the magistral phage preparation principle in Belgium. And in Germany a large clinical study is set up, called ‘phage4cure’, to work towards phage therapy. In Georgia they also use antibiotics, next to their more popular phage therapy, but less often. In Poland a lot of phage research is done as well.

Most important conclusions:

• According to recent papers, AMR is a fast-growing problem.
• Our method would be a major improvement to current methods for detection.
• Sherlock Cas12 could be an alternative for our dCas9.

Follow-up:

• Figure out whether the concentration ranges of dCas9 and the target DNA correspond, using a computer model.
• Try to work on more things in parallel, to get more done in a shorter time.

June 11, 2019 - Derek Young, Medtronic

We met with Medtronic regarding sponsorship. In this meeting, we got some good feedback about how to best convey our ideas to the public.

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June 11, 2019 - Derek Young, Medtronic

A few members of our team went to a meeting with Medtronic regarding sponsorship. During the meeting Derek Young and Soren Aasmul were present. We presented our idea in more detail and they had the opportunity to ask questions and start a discussion.

What we mostly noticed was that at Medtronic, they are very focused on devices. Also, our way of explaining the project can sometimes be unclear for people who are not too familiar with synthetic biology. According to Derek, it was a shame that our project will end after the competition in Boston. However, there are some people from our team interested in continuing the project during their master thesis. This was something to keep in mind when looking for other sponsorship opportunities, as most companies would be more interested in long-term initiatives. Derek also thought that an IP should be considered by the team, this is something we also have been thinking about, but a final decision is still to be made. Lastly, Derek mentioned that it is very important to thoroughly investigate the risks regarding our project, especially the risks that are patient-related.

After the meeting, we discussed the possibility of designing a prototype for our concept. It would be very useful to show people what it is we are doing. Our idea would be more comprehensible to the public by showing them a visualization of our project/research, instead of simply explaining the idea. Therefore, we will try to design a prototype to give people a better insight into our system, maybe in collaboration with Medtronic.

Most important conclusions:

• Companies like Medtronic are more interested in long-term collaborations.
• It is important to investigate all the risks regarding our project.

Follow-up:

• Discuss the idea to apply for a patent.
• We are going to design a prototype to give people a better insight into our system.

June 18, 2019 - Presentation for old iGEM Eindhoven teams

To get some more feedback about our project, we organized a presentation for the previous iGEM Eindhoven teams. Here we presented our project and our progress on all the different parts of the project.

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June 18, 2019 - Presentation for old iGEM Eindhoven teams

To get some more feedback about our project, we organized a presentation for the previous iGEM Eindhoven teams. Here we presented our project and our progress on all the different parts of the project. Everyone thought that our idea and our goal were interesting, but they had some tips on how to improve what we were doing.

The most important point of feedback they gave us what that they noticed that we were only working on improving a part, while coming up with a new part is a requirement for the silver medal. They also gave us some tips on what to do during the Giant Jamboree in Boston. The presentation here shouldn’t be too scientific, and we should find ways to attract people to come to our presentation.

Most important conclusions:

• We have a very interesting idea, but the goal to solve antibiotic resistance is not very unique, so we should focus more on how we are solving it.

Follow-up:

• We are looking into options for a new part.

Figure 3: Jeroen Deckers presenting our project to members of the old iGEM Eindhoven teams.

July 3, 2019 - Dr. Kees Verduin, PAMM

PAMM is an independent laboratory that takes care of microbiological diagnostics for several hospitals and other healthcare providers. They have supported our iGEM team for the past few years, and their expertise in the detection of bacterial infections is particularly interesting for our project. From this meeting, we got some information about the normal procedure in case of a urinary tract infection.

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July 3, 2019 - Dr. Kees Verduin, PAMM

PAMM is an independent laboratory that takes care of microbiological diagnostics for several hospitals and other healthcare providers. PAMM has supported our iGEM team for the past few years, and their expertise in the detection of bacterial infections is particularly interesting for our project. From this meeting, we got some information about the normal procedure in case of a urinary tract infection and other common infections.

The most common causes for a urinary tract infection are a few different types of E. coli, and next to that around 5 other bacteria. When a patient arrives at their general practitioner with symptoms, a first test to detect leukocytes and erythrocytes is carried out, after which a sample is sent to the laboratory and cultured. Then, after a day, a diagnosis can be given. The detection of urinary tract infections is often difficult, partly because there are usually multiple bacteria involved.

Something that takes longer than just this one day is the determination of which antibiotics a bacterium is sensitive to. This now takes up to three days and is, therefore, a process that could greatly benefit from a faster method.

Because of the culturing of the bacteria, and the current methods to then detect the proteins of the bacteria that might be present, the chance that a bacterium is missed is very small.

The number of multi-resistant bacteria that PAMM comes across is very small, and the ones that are found are still quite treatable. This is mostly due to the strict regulations around antibiotics in the Netherlands. In countries in southern Europe and in the US, there is a higher incidence of multi-resistant bacteria and solutions are scarcer.

Most important conclusions:

• False positives and false negatives should be avoided.
• Determining whether bacteria are sensitive to different antibiotics takes quite a long time.
• Our method can simplify the current process of diagnosis and can, therefore, reduce costs and diagnosis time.

Follow-up:

• We can work in PAMM’s laboratories if some work cannot be done in our own labs.
• They are willing to validate some of our experimental studies.

August 2, 2019 - Dr. Lily Frank, ethicist

Lily Frank is a philosopher and an assistant professor of philosophy and ethics at our university. She thinks our project is promising and she had the same idea as we already had about the ethics within it.

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August 2, 2019 - Dr. Lily Frank, ethicist

Lily Frank is a philosopher and an assistant professor of philosophy and ethics at our university. She thinks our project is promising and she had the same idea as we already had about the ethics within it.

The costs of antibiotics will probably be about the same as our detection system. However, people will not need five different types of antibiotics anymore. The costs of our device and one antibiotic or the costs of five different antibiotics will probably not be that different. If we would make our device re-usable, healthcare costs will reduce considerably. In that way, this money can be spent elsewhere.

From a medical ethics perspective, we can give a promise of improvement of health. Considering the previously mentioned example, only one-fifth of the antibiotics will be used, resulting in fewer side effects. In this way people can be treated on a more pleasant way and less other drugs to cover these side effects are necessary, binging us back to the point made about lowered healthcare costs.

Another advantage Lily mentioned was that our device is easy to explain. It is easy to understand how it works and what phages will do within the device. It is for example even easier to visualize than a pregnancy test. This helps with introducing and promoting the device in society, which is very beneficial.

Synthetic biology enables us to create everything one would desire, which might not be ethically justifiable, but it also enables us to cure and heal more easily. This is something Lily didn’t want to make a judgment about in general, but rather about specific applications. The most important thing she told us was that people should not significantly harm others or violate human rights. Altering the genome is not morally wrong, but there is limited knowledge on long term effects. Many things are unpredictable, but when it turns out to be bad in the future, you cannot change it back.

It is unethical for companies to oppose phage therapy so their marketing of antibiotics will continue, when the motivation of the company is just to keep their profits up. Whether there is a correlation between antibiotic resistance and industrial sales, cannot be answered, therefore more information about the cash flow within the healthcare industry is needed.

Another ethics perspective is media ethics. It is unethical for a talk show to only let “pro-phage” people speak and only show the benefits, since this creates a delusion. Researchers should only communicate scientifically and provide the full picture including the disadvantages, especially when they are promoting phage therapy on television.

We wondered if policies should change at a same rate as the fast developments within the medical technology. Lily’s answer to this was that this would be impossible since scientific development goes very fast. It is good to have regulations so new drugs are tested comprehensively. Even if unapproved drugs are promising, it is illegal to use them because regulations try to protect society and minimize risks. Making such drugs available for general usage might thus be dangerous. However, in some cases, using them for an individual patient who might be out of other options is reasonable.

A problem with approving phage therapy in the Netherlands is that not enough research is done yet. However, no one is starting research either, because the costs for research don’t outweigh the money earned in the end. Therefore, the government could maybe make a grant for people wanting to do this research.

Most important conclusions:

• Lily confirmed our prior thoughts about ethics.

August 14, 2019 - Evelien Kampert, RIVM

Via RIVM we came in contact with Evelien Kampert who is now a biosafety officer at the RIVM. Previously she worked at the University of Utrecht for Fabagen (Phage bacteria genetics) where she encountered the identification of bacteria. During a phone call she explained to us how they used phages for this identification and how our project would be an improvement to that technique.

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August 14, 2019 - Evelien Kampert, RIVM

Via RIVM we came in contact with Evelien Kampert who is now a biosafety officer at the RIVM. Previously she worked at the University of Utrecht for Fabagen (Phage bacteria genetics) where she encountered the identification of bacteria. During a phone call she explained to us how they used phages for this identification and how our project would be an improvement to that technique.

Evelien Kampert worked a lot with the formation of E. coli mutants with the use of UV light at Fabagen. However, different properties of these mutants needed to be checked, and one of these was the identification with the use of bacteriophages.

The identification technique works by first culturing bacteria on agar plates. After the plates had dried, they added loose droplets of phages. In this way you could see whether a bacterium was resistant for the phage, because you could see the lysis of the bacteria with the naked eye. The phages Evelien Kampert has used most were the Lambda phage, PhiX174 phage, and the T1-7 phages. However, this method still needed overnight time before identification could take place.

After explaining our own detection method, Evelien Kampert gave us a few tips and remarks about our device:

• Be sure that you have enough bacteria in your sample, otherwise the lysis will not be enough for detection.
• Your method needs to be better than PCR, it is important that you have an improvement of previous systems.
• Background signal is a big problem, take care of that by for example adding a purification step, this to exclude false positives.
• You still do not know the origin of the infection by using our detection system.
• What is the influence of the system on the choice of antibiotics? Is there a one to one connection?

In general, Evelien Kampert sees potential in our system. However, a lot of obstacles have to be tackled. The double improvement of a faster detection and a more specific application of antibiotics would be a great benefit that could have a great impact in America. Mostly because the regulation of antibiotics is, in general, already well under control in the Netherlands.

Most important conclusions:

• The old detection method took a long time. Our system would be an improvement.
• Evelien Kampert gave a lot of tips that are helpful for our device. For example, adding a purification step would be helpful for the background signal in our device.

August 17, 2019 - Meetup iGEM Leiden

The iGEM teams of Leiden and Delft organized a meetup on of August 16 and 17 for all Dutch iGEM teams to present their progress and get feedback on their presentation.

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August 17, 2019 - Meetup iGEM Leiden

The iGEM teams of Leiden and Delft organized a meetup on of August 16 and 17 for all Dutch iGEM teams to present their progress and get feedback on their presentation. We visited only on Saturday the 17^th. The day started with presentations of all teams that were present, including our own presentation after the break. This gave us a good insight what the other teams were doing with their projects and of how far they were with their project. From this we also concluded that we weren’t as far behind on schedule as we thought compared to the other teams. Before the break, Niek Savelkoul, European ambassador of iGEM, gave us some additional tips for our presentation in Boston: It would be best to tell a personal story that people can relate to. Human practices should also be integrated into the presentation. For example, expert meetings and their impact should also be discussed. Another important part to include in the presentation is the safety aspect of the project. He also told us that, when creating a device, it’s really good to have a prototype to show to the people during the presentation. Some practical aspects were to practice in the room in Boston with beamer and microphone where you have to present so you won’t be in for any surprises during the actual presentation. Keeping gender balance among your 2 to 3 presenters is also a plus. Lastly, he told us to hand out goodies in Boston so that people will constantly be reminded of your project.

We also received feedback on the actual content of the presentation from one of the jury members who was present. Firstly, she noted that we didn’t have a title for our presentation/project yet. We had to make our problem more personalized and start with the problem, then the numbers. She really liked our visual modular workflow, but was not a great fan of the blue background with black text on it, which we also noticed ourselves already. Furthermore, she wanted to bring the safety and risks of using phage therapy more to the foreground. Lastly, she advised us to visualize our human practices part more by showing models instead of just telling the suggestions of stakeholders. She also thought it could be nice to start with the phage therapy use in Europe.

In the afternoon we had a crazy88 in the city center of Leiden with mixed teams to get to know the other teams a little bit better, which was a lot of fun. Unfortunately, none of our team members won a prize.

Most important conclusions:

• Our current progress is similar to that of other teams.
• The presentation is quite good already.

Follow-up:

• Adjust presentation according to the feedback.
• Come up with a project name.

Figure 4: Eva Hanckmann presenting our project at the iGEM meetup in Leiden.

August 23, 2019 - Dr. Stijn Konings, Catharina Hospital, Eindhoven

Stijn Konings is an internist-nephrologist working at the Catharina hospital Eindhoven. He often sees patients for who a quick determination of the specific type of infection would allow specific treatment to start off sooner, improving the prospect for patients especially in cases with seriously aggressive S. aureus bacteraemia.

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August 23, 2019 - Dr. Stijn Konings, Catharina Hospital, Eindhoven

Stijn Konings is an internist-nephrologist working at the Catharina hospital Eindhoven, whom we contacted to discuss his experiences with (AMR) bacterial infections and his thoughts on our proposed detection principle.

As nephrologist, Stijn Konings mostly encounters infections related to dialysis treatment for renal failure. Bloodstream infections resulting from haemodialysis treatment with an intravascular catheter, often result in the serious condition called line sepsis. Also, peritoneal dialysis comes with a serious risk of infection induced peritonitis. These infections are mostly caused by Staphylococcus bacteria, with the S. Aureus being very dangerous and often multi-resistant (MRSA), while the S. epidermidis is less of a concern. Unfortunately, it takes at least 1 to 3 days now to differentiate S. Aureus from S. epidermidis, and in general to identify any bacterial species, due to the required culturing time. Cytograms are used to quickly discover the presence of bacteria and, if present, to determine whether these are gram-positive or -negative. Unfortunately, this assay has a relatively high false-negative rate and cannot identify the specific bacterial species. To avoid facilitating antimicrobial resistance, doctors often wait for the culturing results before starting treatment, to allow to use a more specific antibiotic regimen instead of general broad-spectrum ones. However, taking the life-threatening danger of a septic condition into account, it would be highly beneficial to be able to start specific treatment earlier on.

That is where our proposed detection method comes into mind. Detection of the specific bacterial species within hours instead of days would allow an early start of specific antibiotic (or phage based) treatment, with the potential to significantly ameliorate a septic patient’s prognosis. Stijn Konings acknowledged that detection within a few hours would indeed really be a major improvement in diagnostics. The ability to discern S. Aureus from S. epidermidis within such a short timeframe would especially be interesting for Konings’ field. We explained our method is a screening method, not allowing fully universal identification of all existing sorts of bacteria, however with the right pre-set adapted to the specific field of application (in this case catheter associated infections), it allows differentiating the commonly found bacteria. Stijn Konings notes that the method should work in blood(plasm) for applicability in his field, which might not be trivial and harder to accomplish than in urine for instance. On the other hand, blood infections are often significantly more dangerous and acute conditions than urinary tract infections, which would make successful blood-based detection a major plus of the method.

Konings correctly notes that antibiotic susceptibility testing and/or resistance checks would still be required next to our proposed method. We could look into extension of our technique to include detection of resistance genes for example. Yet, Konings thinks our method would still be a major improvement to diagnosing bacterial infections without this resistance screening. Allowing rapid detection and differentiation of Staphylococcus species for example, would be useful for making treatment decisions, promoting the use of targeted therapy and thereby mitigating the AMR problem.

Regarding his experience with AMR in general, Konings acknowledged this is indeed a growing problem, although in The Netherlands it is still relatively well manageable. He mentioned about 10 to 15% of the urine E. coli are resistant to ciprofloxacin for example. Still, most serious AMR cases he encounters in his life as medical professional concern patients who are from other countries or visited a hospital in for instance southern Europe, where AMR is a much more serious problem already.

Most important conclusions:

• Our diagnostic method would allow starting more specific treatment of an infection up to 3 days sooner, which could make a significant difference for the patients’ health.
• AMR is a growing problem worldwide, but there are major differences in the degree of managing it among countries.

Follow-up:

• Figure out whether detection and differentiation of S. aureus and S. epidermidis in blood would be feasible with our proposed method.
• Think about potential extension of the technique to also include identification of resistance genes.
• Arrange a meeting with doctor Ammerlaan, an infectiologist colleague of Stijn Konings, for a more elaborate discussion on AMR, phages, and the potential of our proposed method.

August 30, 2019 - GD Animal Health

During a meeting with the research & development team of GD Animal Health to talk about the possibilities for a collaboration, we discussed the differences in antibiotics use between animals and humans, and how our project could benefit GD Animal Health.

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August 30, 2019 - GD Animal Health

During a meeting with the research & development team of GD Animal Health to talk about the possibilities for a collaboration, we discussed the differences in antibiotics use between animals and humans, and how our project could benefit GD Animal Health.

The past 10 years, the use of antibiotics in animals has decreased by 50%. GD Animal Health is always working on trying to decrease and optimize the use of antibiotics. The Netherlands and Scandinavia are a lot better at controlling the use of antibiotics than many other countries in Europe and the rest of the world. Also, while a lot of sources might suggest otherwise, it has been proven that there is no correlation between the development of antimicrobial resistance in animals and humans.

We also asked about the use of bacteriophage therapy in animals. Experiments are being done for this, but it is not widely used. This is partly because there is a lot less money to spend for animal health care than for human health care.

Some tips that we got regarding our project are that we should think about that the samples that we will test with our system might be polluted and therefore more difficult to test than a perfectly purified test sample. Also, our system is only useful when it is better and/or faster than current methods, like PCR, so we should compare our results to that. Our detection system would be more useful if it could measure quantitatively and not just qualitative.

GD Animal Health is mostly interested in the detection part of our system, because, with only a little tuning, this could be used for other applications as well. Interesting applications for them would be to distinguish between resistant and non-resistant bacteria, which means you must look at the DNA of the bacteria instead of the bacteriophage. Other applications could be to detect RNA instead of DNA, or to detect viruses instead of bacteria. Our system would also be interesting for the testing of food and water.

Most important conclusions:

• There is no correlation between the development of antimicrobial resistance in animals and humans.
• The detection part of our system is most interesting for further development for other applications.

Follow-up:

• We will look into the possibility of working together to exchange knowledge, so that we can both benefit from each other’s work.

September 18, 2019 - Dr. Heidi Ammerlaan, Catharina Hospital, Eindhoven

On Wednesday September 18, we went to the Catharina Hospital in Eindhoven to meet with Heidi Ammerlaan. She is an internist-infectiologist. During this visit they talked about AMR in the hospital and how the process of bacterial detection works.

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September 18, 2019 - Dr. Heidi Ammerlaan, Catharina Hospital, Eindhoven

We went to the Catharina Hospital in Eindhoven to meet with Heidi Ammerlaan. She is an internist-infectiologist. In 2010 she did a promotion research about antimicrobial resistance (AMR) where she focused on the influence of infections as a consequence of resistant bacteria.

Currently, when a patient enters the emergency department with signs of an infection, the source of the infection is determined. The first step towards finding the source is performing a general blood test for inflammatory factors, a urine sample to test for impurities and sometimes a lung X-ray. When signs of infections are found in these first tests, subsequently urine and blood samples are sent to the PAMM foundation for culturing to check which bacterial strain is causing the infection. Sometimes the results come back within 1.5 days, but most of the time it takes around 3 days for the results to return to the hospital. Often no positive results are found during culture, and if no positive test results are found within 7 days, the test is confirmed negative.

When we asked her about our detection system, she confirmed that it would be useful to have a faster detection of the bacterial strain and is positive about our method. She indicated that PCR is currently used as a fast detection method, but it is very sensitive to false positives. Therefore, she advised us to limit false positives and false negatives. In addition, she emphasized that the costs of our system are of importance to specialists. PCR tests for specific bacterial strains are often quite expensive, so it would be beneficial if the costs of our detection system would be lower than for PCR.

Currently, other fast tests are available that can determine whether you have a certain infection. They are very specific for one type of infection like for Legionella pneumophila and Streptococcus pneumoniae. However, these tests still take around 24 hours, and are not very modular. So, our detection system could be an improvement both in detection time and modularity. One POC test is already in use to detect Influenza at the intensive care and this test takes 1 hour to detect the influenza bacteria.

Furthermore, we asked her opinion on phage therapy. In her opinion, phage therapy could be a good alternative to antibiotics for some patients. However, it cannot be used as widespread as antibiotics, since it is often administered locally. She emphasized that it is good that research is being conducted to find alternatives for antibiotics because of the growing health threat.

Most important conclusions:

• When false negatives can be removed, Heidi confirmed that our detection method would be useful.
• Phage therapy would be a good alternative for antibiotics after more research.

Follow-up:

• Use the site of European Centre for Disease prevention and Control (ECDC) for depicting the spread of AMR.

September 25, 2019 - Jitske Stalpers, PAMM

PAMM is an independent laboratory that takes care of microbiological diagnostics for several hospitals and other healthcare providers. PAMM has supported our iGEM team for the past few years, and their expertise in the detection of bacterial infections is particularly interesting for our project. We got the opportunity to join pathologist Jitske Stalpers on her daily routine within the PAMM laboratories and thus see how microbiological diagnostics are currently performed.

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September 25, 2019 - Jitske Stalpers, PAMM

PAMM is an independent laboratory that takes care of microbiological diagnostics for several hospitals and other healthcare providers. PAMM has supported our iGEM team for the past few years, and their expertise in the detection of bacterial infections is particularly interesting for our project. We got the opportunity to join pathologist Jitske Stalpers on her daily routine within the PAMM laboratories and thus see how microbiological diagnostics are currently performed.

Presently, PAMM gets patient samples from five different surrounding hospitals and several general practitioners. The transport of these samples from the patients to the centralized laboratory of PAMM already costs some valuable time. The samples to be analyzed for bacterial infections are then automatically plated on the corresponding growth medium and cultured for sixteen hours. After this, photographs are taken and these are consequently analyzed by the pathologist. If there are no cultures to be seen, the plates are cultured for another day before they are determined negative. If cultures are observed, the pathologist can sometimes immediately determine the source of the bacterial infection, while in other cases MALDI analysis is needed for determination. After determination of the bacterial source, the antibiotic susceptibility (AST) is tested using the VITEK. This AST takes an additional day which means that it takes at least two days before there is a conclusive result about the antibiotics that can be used to treat the bacterial infection of the patient.

In the short time that we were present, already a few results concluded the presence of ESBL bacteria in the samples. When asked, Jitske told us that the number of multi-resistant bacteria she comes across is increasing heavily and that is thus becoming more and more of a problem. There even have been results in the PAMM laboratories where one specific strain of bacteria was only susceptible to one antibiotic.

Most important conclusions:

• Source of bacterial infection can only be determined after one day (transport + sixteen hours of culturing).
• The antibiotic susceptibility test takes an additional day.
• The number of multi-resistant bacteria observed in the PAMM laboratories is increasing and is much higher than say ten years ago.

October 4, 2019 - Den Eelder, dairy farming and dairy company

Except for human health, AMR is also a big problem in animal health. Therefore, we went to Den Eelder, a dairy farming and dairy company in the Netherlands. We talked with Pieter Rozendaal and Ernst van der Schans about the use of antibiotics and the influence of AMR on their dairy products. We also talked about whether our system would be helpful in their company.

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October 4, 2019 - Den Eelder, dairy farming and dairy company

Except for human health, antimicrobial resistance (AMR) is also a big problem in animal health. Therefore, we went to Den Eelder, a dairy farming and dairy company in the Netherlands. We talked with Pieter Rozendaal and Ernst van der Schans about the use of antibiotics and the influence of AMR on their dairy products. We also talked about whether our system would be helpful in their company.

In dairy farming, infections are often present. Last year, 12% of the cows from Den Eelder got mastitis. However, the national average lies at 25%, which indicates the frequency of occurrence. Back in the day, every cow received antibiotics when she got an infection, but this is highly reduced in the present. Since 2012, every farmer has to follow a treatment plan that is prepared by the veterinarian, before antibiotics are administered. This highly reduced the use of antibiotics and resulted in a reduction of AMR in dairy farming.

The diagnostics of infections is done in different ways. Every 6 weeks, the milk of every cow is tested on percentage fat, percentage protein, and cell number. If the cell number reaches a number above 150.000, there is a high possibility of infection. A second way to diagnose is by visuals. With mastitis, the udder is red and swollen and the milk is a bit off-color. These diagnoses are determined by the farmers themselves and treated following the treatment plan. However, they are not 100% sure which infection they are dealing with.

When an infection is not gone after the first treatment, and more cows suffer from the same infection, new samples are sent to GD Animal Health in Deventer. Like in human health care, it takes 3 days before the farmer receives the results and can start an alternative treatment. Therefore, we proposed the use of our device to reduce the detection time to 1 hour. Pieter Rozendaal agreed that reducing the detection time would improve the treatment of the infection. He also mentioned that it would be an economic benefit for the company. Because earlier detection would mean earlier treatment and earlier recovery of the cow, which means that the milk can be used earlier for production.

Pieter also mentioned that there are third-generation antibiotics that are working really well at their farm. However, due to regulations, these third-generation antibiotics can only be used after the first two generations failed. A test that could determine the origin of infection within 1 hour, would therefore save them some time. Also, the spectrum of antibiotics that is administered can be reduced using our system.

Still, there are a lot of accusations to cattle farming about the spread of AMR. But Pieter mentioned that, because of the better control due to the treatment plan, and a reduction in AMR in their dairy farming company, they are not the ones to blame. From a discussion about the use of antibiotics with the Utrecht University, he heard that pets get AMR from close contact with humans and not the other way around. And there is no such close contact within dairy farming.

At last, we asked whether phage therapy could be a solution in their company. Ernst van der Schans never heard of the use of therapy for dairy farming, but they do have phage infections in their dairy company. For example, for the production of buttermilk, lactic acid bacteria are used. When contamination with phages occurs they have to change to other lactic acid bacteria until the phage infection is removed. But because of the specificity of phages, this wouldn’t be a problem when applying phage therapy.

Most important conclusions:

• Reducing the detection time would help in the faster and more specific treatment of cattle.
• The problem of AMR is not due to bad use of antibiotics in dairy farming.
• Phages can cause infections in the production of dairy products.

General practitioners

One group of important stakeholders for our project are the general practitioners. Our system can be used to quickly test urine or blood samples on the presence of possible bacterial infections. While general practitioners now have to send patients’ samples to a laboratory and wait at least a few days to get the results back, our point-of-care detection system can easily be used by general practitioners and produce a diagnosis within a few hours. This diagnosis might then change the treatment that the general practitioner will prescribe for the patient.

In order to confirm our thoughts about how our detection system could benefit both general practitioners and patients, we talked with a few general practitioners and asked them about their experiences with bacterial infections and how our detection system could help in these situations.

The four general practitioners that we talked with all differed in age and experience, of which the youngest has just half a year experience as a general practitioner. The most experienced doctor, dr. Vink, has 50 years of experience. One of the doctors, who works in Belgium, has 31 years of experience and the last one has 22 years of experience.

The given answers regarding the occurrence of bacterial infections were somewhat different, the most experienced doctor, dr. Vink, estimated the occurrence of bacterial infections to be 10-30% of his patients, which wasn’t a lot compared to the others, who saw bacterial infections every day. They all believed the amount of infections remained constant through the years. The most common bacterial infection was the urinary tract infection.

The procedure on how to treat the bacterial infections varied a lot. Both the Belgian doctor and dr. Vink often empirically decided how to proceed. They both gave antibiotics sooner to people who had chronic problems with infections, or to people who were more sensitive (elderly, COPD, diabetic and babies). The other two doctors both follow protocols, which tell them what the guidelines are for starting with antibiotics and the choice of antibiotic.

The waiting time for a sample to be tested varied from the same day to a week. Dr. Vink also mentioned that he didn’t make these samples too often, but when he did, most often the patient would already be better in the meantime, or already be dead, because of the long waiting time back then.

All the doctors saw an increase in bacteria that are resistant for antibiotics. The cause of this resistance is mostly caused by prescribing antibiotics too short with a too low dosage, according to dr. Vink. What he also saw on weekend shifts, were other doctors prescribing a sweet penicillin drink to children with a cold, which he didn’t give as he foresaw the danger of overusing antibiotics.

‘Antibiotics are like the plague
in the hands of the doctor’ - Dr. Vink

All the doctors think the future of antibiotics doesn’t look too good and according to dr. Vink, ‘Antibiotics are like the plague in the hands of the doctor’. Having a second option to fall back on would be very useful. They all thought our point-of-care detection method would be very useful, mainly Dr. Vink was very enthusiastic and would really want to have a device like that. According to the doctors it would help with prescribing more specific antibiotics and would result in less waste of antibiotics. Also, the service towards patients would improve much and they would be more reassured to get a good and specified treatment. The only thing some of them were skeptical about, were the costs. Our youngest doctor mentioned that giving a broad spectrum of antibiotics mostly works, and that she thought our device would be most useful when there would be an infection which has returned a few times. This was in contrast with the other doctors.

Responsible Research & Innovation

Responsible Research and Innovation (RRI) is the central theme of Horizon 2020, which is the biggest EU Research and Innovation program ever implemented by the European Commission [1]. Due to past approaches, the EU policy faced difficulties dealing with issues that was ethically and socially entailed as a result of science and technology. RRI is a framework that gains increasing recognition within both the academic and the EU policy world, showing its importance [2].

Therefore, we investigated how RRI could help us to form our project. One of our team members followed a minor called Responsible Innovation in a Global Context, where the concept was first introduced by Assistant Professor Johanna Höffken from the group Technology, Innovation and Society at Eindhoven University of Technology.

First, we asked ourselves what it means to be responsible within our project. A few key points are mentioned below:

• Realizing the impact on society of our project.
• Determining all the uncertainties that are related to our project.

According to Shomberg, who is a EU bureaucrat, RRI is defined as follows: ‘Responsible Research and Innovation is a transparent, interactive process by which societal actors and innovators become mutually responsive to each other with a view to the (ethical) acceptability, sustainability and societal desirability of the innovation process and its marketable products (in order to allow a proper embedding of scientific and technological advances in our society)’ [3].

Owen, Stilgoe and Macnaghten, who are academic scholars of RRI, reframed responsibility and approaches focusing on 4 dimensions in the article ‘Developing a framework for responsible innovation’ [4]. In the article it is written that ‘Responsible innovation means taking care of the future through collective stewardship of science and innovation in the present’, which encouraged us to understand and think of what kind of future we want to create, recognizing the power science and innovation have, to transform the future.

Implementing the 4 dimensions into the process of our project helped us to understand that science and technology is not only constituted technically but also socially and politically.

Anticipation

This involves improving foresight, being mentally prepared and aware to recognize uncertainties in the future. Asking ourselves the question; ‘What if’? Without making predictions, because we may not always predict outcomes easily and predict what can happen when certain actions and choices are being made, in advance. It is hard to draw lines and blame where the impact of innovation started. However, it is possible to anticipate and envision impacts our project could possibly have. In every project it is, therefore, very important to also be aware of the uncertainties that are present in the project. In addition, with every choice and action we make comes assumptions and some may seem very logical. But there is always the possibility that these assumptions are invalid when tested. Perhaps leading towards severe consequences.

We started with an idea of how we can implement our project. We have an idea of how to make the ‘perfect’ device, but it might be better to change some parts, depending on how it will be used. Also, every part is tested before it is implemented. By being aware that there will be uncertainties in how our device will be perceived in the future, we make sure to include stakeholders' opinions. Such as that time is an important aspect to incorporate into our thought process about the device. However, even with their included voices, we keep in mind that we are not able to predict the outcome and impact, keeping all options open. We think our detection system will be very useful for general practitioners for example, but we cannot guarantee that they will actually use it and benefit from it. Therefore, with the help of anticipation we incorporate a certain mindset by questioning our work in order to keep involving experts, stakeholders and try to recognize uncertainties in the future.

Reflexivity

This part is meant to make scientists aware of what they are doing. Basically, a mirror is held to one’s own activities, commitments and assumptions. By doing this, limits of knowledge can be recognized within the project by understanding the concept of the known, the known unknown and the unknown unknown. Keeping in mind that technology determines what we know beyond our own senses. Therefore, we reflect on what we already know, we know what we don’t know, and we reflect on underlying assumptions, values and the understanding that not all issues are universal. We reflect not only within our own team but also take the opinions of other stakeholder into account to increase the capacity of reflection within our project. Keeping in mind to always reflect with inclusion of our professors, research funders, institutions etc. This helps us to reflect not only with our own values but also the values of other stakeholders.

With our team we reflect on our own work for the project. For this reflection we take stakeholders’ opinions into account. After each conversation with a stakeholder, we write down what the most important feedback is from the stakeholder that we could incorporate in our project. On our Stakeholders page the most important conclusions and follow-ups can be read for every stakeholder we have spoken to. Each time we make a decision, whether it is in the lab or deciding to contact a stakeholder. We think about what the goal is of that action, and whether that goal is actually important enough to take the action. During the process, we realized that reflecting on our work and the decisions we make is very important, because in the beginning sometimes a decision was made that turned out to be unnecessary. So, we started to take more time to reflect. Also, we reflect within our team on our teamwork, communication, and our behaviour within the team.

Diversity and Inclusion

This means introducing new voices, consensus conferences, citizen juries, focus groups etc. In order to be responsible, research & innovation must be inclusive. It is therefore necessary to include voices into goals and trajectories of the innovations. This means that we must be open about our project. From the beginning we involved and engaged a wide range of people into our project and throughout the process to form and give a more useful project that is of higher and a broader aspect of knowledge. We keep in mind to organize events where stakeholders and public can voice their opinions and question our work. Which helps us to make decisions not only by our own team but by participation of a greater inclusion. Because the core of collectives is to have sense of common purpose. In our project we engage all actors because we have a collective responsibility. The actors who are involved with us are all sharing the same believes and desires.

Our project involves a lot of stakeholders. To get the full story and take into account all the different perspectives, we talked with a diverse group of stakeholders, ranging from people in the industry of human health care, animal health care, and the diary industry. We talked with people who work in the field of bacterial infection detection, people who work with bacteriophages, and people who work in the field of developing medical devices. We also talked to possible users and people who could benefit from our device. But we also tried to include people who are possibly less positive about out project and the possible results, who might even be against the development of a device like ours. Without result, the people we tried to include were the people in the industry of antibiotics development, who might lose a part of their profit when our device works. For the opinion of the general public, we made a questionnaire to ask people about their experiences with antimicrobial resistance, the use of antibiotics and their knowledge about bacteriophages. With all these stakeholders together, we gained perspectives from technology, industry, politics, ethics, and society. All of these interactions are explained on our Human Practices pages.

Responsiveness and Adaptive Change

This means to be able to ‘modify modes of thought and behavior’. This is important when the circumstances change, because in the past negative consequences occurred due to scientific and innovative work not responding and adapting towards changing circumstances, different responses from the public or stakeholders. However, if people do not take risks anymore, there won’t be innovations anymore. Therefore, it's important to respond and include the public and engage with stakeholders so we also spread responsibility. Keeping in mind to answer, acknowledge and recognize the moments when we do not have enough knowledge or control.

When we started designing our project, we had an idea of how we could carry out our project and what would work best. However, during the course of the project we reflected, talked with stakeholders, and organized events to gather opinions, which gave us new insights. We always try to respond to these insights and act accordingly. We adapted to changing environments and changing circumstances, by considering different opinions. For example, in the beginning we were focused on developing a proof-of-concept, but halfway through our project, with the input of our stakeholders, we realized that it was also important to show what we could achieve in the future with this proof-of-concept, so we decided to design a device. Also, within our team we adapted according to the strengths of the different team members, which caused a change in the division of tasks within the team.

References

1. Wynia, S. (2017, March). What is Horizon 2020?. Horizon 2020. European Commission. Used on september 19, 2019, from https://ec.europa.eu/programmes/horizon2020/en/what-horizon-2020.
2. European Commision Decision. (2019, March). EN Horizon 2020. Work Programme 2018-2020. 13. Europe in achanging world. Inclusive, innovative and reflective societies.
3. Von Schomberg, R. (2011). ‘Prospects for Technology Assessment in a framework of responsible research and innovation’ from: Technikfolgen abschätzen lehren: Bildungspotenziale transdisziplinärer Methode. P.39-61. Wiesbaden: Springer VS .
4. Stilgoe, J.; Owen, R.; & Macnaghten, P. (2013). Developing a framework for responsible innovation. Research Policy, 42(9), 1568-1580.