Stakeholders

To obtain more insight in the feasibility of our idea, we talked to many experts within different fields. Among the people we approached are doctors, researchers, students, but also people working in non-academic fields such as at ministeries and professional advisors. Each of them was invited to give their perspectives on our work. We also wondered if they could see the benefits of our device within our application scenarios and if they had any other suggestions for usage. Moreover, we gave them space to criticize our idea, and thereby advise us about aspects of our design that could be perfected. With their involvement, we could further develop our ideas. A short overview of each talk is given below.

General

RIVM & Rathenau

RIVM is the national institute involved in regulation of safety and environment. The Rathenau Institute is involved in the consideration of technological advancements and their role in society. Both institutes regularly experience the clash that occurs when technological novelties are presented to a poorly informed public. To promote dialogue between society and technological researches the RIVM and Rathenau Institute together organized a symposium about synthetic biology and its role in society.
The iGEM-teams of the Netherlands had an active role in the organization of the symposium and were given an opportunity to present their projects to a diverse audience (consisting of amongst others employees of the RIVM and Rathenau and ministries). The presentation was followed by a discussion about societal problems that play a role when considering synthetic biology. Read more on this event here:

The RIVM is the government body responsible for improving public health and providing a clean and safe environment.

We presented our project to policymakers attending the SynBio convention and held a discussion afterwards.
Bureau GGO - Dr. E. (Eric) van den Akker – Risk assessor at Bureau GGO of the RIVM

Goal: Learn more about regulation involved in the application of GMOs in the environment.
Approach: We spoke to Eric van den Akker from Bureau GGO and who is involved in the assessment of GMO usage. Thereby we asked him what procedures are applied in the judgment of GMO risks. Also we asked him about the possible problems we could encounter with our device and we asked for advice to overcome these problems.
Result: Dr. Van den Akker could tell us about the procedure of getting a license for GMO usage outside the laboratory. Therefore one needs to apply for a permit to introduce bacteria into the environment. COGEM will than evaluate the application and give permission or not. Important hereby is that we use E. coli K12, which is considered relatively safe. Other instances involved are the CCMO and the EMA. The CCMO tests ethical aspects of medical innovations and EMA is involved in regulation involved in genetic modification. Dr. Van den Akker advised us to give early notice of what our plans are to these committees. They can give further advise and can make it easier for the device to be accepted. Further he could tell us that thanks to our project he met with Claudette de Vries, an expert about safety around medicinal products and medical devices of the RIVM, for the first time. They could easily see a collaboration grow from this meeting.

We visited Bureau GGO to talk through the GMO regulations
Drs. V. (Virgil) Rerimassie - Legal expert working for the Rathenau Institute and involved in research towards the ethical, social and juridical aspects of novel technologies
Goal: Give some direction to the policy and practices part of our project.
Approach: We met with Drs. Rerimassie who works at the Rathenau Institute. We presented him our ideas and he helped us explore the application options for our device and helped us in making a plan of approach to present our device to the public.
Results: Drs. Rerimassie motivated us to take a step backward from our project and look at our device as a source of opportunities. Thereby we should consider what societal problems we can solve using our device and what needs there are in society. He encouraged us to listen to the requests of society. Thereby he made the comment that we should also consider other solutions to these problems and we should consider if our product is really the best option. Hereby he helped us to broaden our perspective, which helped us to define our application scenario’s. All in all a useful conversation in the early stage of our project development.
RIVM Regelgeving

Goal: Learn more about regulation involved in medicines and applications of new technologies in the human body.
Approach: We spoke to two employees of the Centrum of Health Protection- Department Product Safety: Claudette de Vries and Robert Geertsma. They informed us about existing legal.
Result: They could tell us that regulation is different for medicines and medical devices. Thereby they referred us to the different laws existing for both aspects of medical interventions. This distinction is useful to make a division between external and internal usages of novelties. One of the differences is that clinical trials are obligatory for medicines and are not included in regulation for medical devices. When we proposed our idea about a device making use of GMOs to track diseases in the intestines, they could tell us that this is considered advanced therapy and new rules apply for that. Important for this application is furthermore that regulation in the usage of GMOs is currently changing.

Intellectual Property Rights

A possible obstacle for our design is the fact that we make use of aptamers as one of the main components; many of the discovered aptamers are currently still patented. Therefore, it was interesting to explore if this could pose any further problems in the future. Therefore, we contacted some experts on the area of patent law. An overview is given below:

Ir. P.H. (Peter) van Dongen - RVO/Agentschap NL - Patent advisor for universities and technological institutes

Goal: To learn more about the basic principles behind patent law and learn more about what we should pay attention to in our own device.
Approach: We spoke to Ir. Van Dongen, who is very experienced when it comes to patent law. We asked him what rules and exceptions there are when it comes to intellectual property rights. And we asked if he could foresee any trouble in the use of aptamers in our design.
Result: Ir. Van Dongen could tell us that patents are granted to any scientist who applied for it and who came up with a novel invention that was never earlier described anywhere in the world, that is not obvious and that could be exploited economically. Hereby it is important to consider that patents are granted per country and it might not be economically favourable for some companies to apply for a patent in small countries like the Netherlands. Patent keepers need to pay tax for the patent they hold in each country, so sometimes it is not beneficious to have a patent-right in each country. Once a company/institute has patent on a specific invention, it has rights to exploit this product economically for 20 years. People can buy the patent or ask for a license, in which case part of the profit is directly transferred to the company who owns the patent. Ir. Van Dongen doesn’t foresee much problems in our research. He could tell us that there is an exception to the patent law when it comes to the use of a product for scientific research. Only if we were to introduce our device to the market we would encounter patent regulation.
Ir. Annika van Rosmalen - Responsible at HollandBio for communication about bio-based technologies

Goal: Get some insights into regulation involved in bio-based technologies like ours.
Approach: We talked to Ir. Van Rosmalen about the potential of our device. Since Ir. Van Rosmalen works at HollandBio, a Dutch association for companies involved in the production of bio-based technologies, she could tell us more about policies and opportunities within this field of research. We explained her about our project and asked if she could foresee any difficulties in practical, but also in the legal perspective.
Result: Ir. Van Rosmalen was quite enthousiastic about the idea of a quick and easy detection device. She advised us to further emphasize the advantages of using bacteria in order to avoid a lot of ethical complaints.
About patent regulation she could tell us that the 20 years of patent rights usually only give the patent holder only 15 years to earn back his/her expenses. This is because an application for patents on different aspects of the design is made at the beginning of the research. However usually it takes at least 5 more years for the research to be published. One other important aspect is that the patent-holders themselves are responsible to keep check of any illegal use of their product. This is not supported by any other agency. Therefore it takes quite some work to keep your patented product safe.
Patentpunt - Mr. R. (René) de Torbal – Consultant in patentdistribution working for Patentpunt

Goal: Learn more about existing patents for aptamers.
Approach: We contacted René de Torbal, working at a consultancy for intellectual property rights called Patentpunt. We informed if he was aware of any patents distributed for aptamers in the Netherlands.
Result: Mr. De Torbal could help us search for patents that had been granted in the field of aptamers. He was open for any further questions about patentregulation.

Existing biosensor methods

With our sensor device we want to find a way to produce a universal sensing method. Therefore it is interesting to look at requirements for sensor systems and the techniques other sensor systems use. To learn more about sensor techniques we spoke with Dhiredj Jagesar, working for DSM (a dutch institute involved in the application of scientific researches in health, nutrition and materials) and involved in the development of one of the most frequently used tests in livestock: the Delvo Test. Furthermore we talked to Menno Prins, professor at the university of Eindhoven, who is very much involved in research towards new sensing techniques. Short summaries of these talks are presented below:

D. (Dhiredj) Jagesar – Scientist working for DSM, in 2006 finished his PhD thesis about “Intercomponent Interactions and Mobility in Hydrogen-Bonded Rotaxane”

Goal: Learn more about detection methods making use of microorganisms.
Approach: We talked to Dhiredj Jagesar about the development of the Delvo test that he was involved in. Also we asked Dr. Jagesar if he could give feedback on our idea.
Results: During the talk with Dhiredj Jagesar we learned about a test that made use of bacteria as basis for detection, but still used these bacteria in a completely different fashion. The Delvo Test makes use of bacterial growth as an indicator of the presence of antibiotics in milk. Therefore this test doesn’t make use of modified bacteria, but simply exploits their intrinsic capacity. Since dr. Jagesar was involved in the production of the test he could tell us more about the requirements that need to be met before bringing such a device to the market. DSM performed as merchandizer of their product. Therefore they performed extensive internal validation to be able to present the customer with a decent product. To gain credibility also external validation of the product was performed. Dr. Jagesar however opted that our product would probably have to deal with different regulation, since it involved the use of modified organsims. Finally we requested dr. Jagesar to give some feedback on our device. Thereby he emphasized that we should be able to defend the use of bacteria in a sensor-system and he referred us to research on different sensor-systems as comparison. Furthermore he had some concerns about the use of our system in the human body. Thereby he warned for possible immune reactions and competition with other “naturally-occurring” bacteria.
Prof. dr. ir. M.W.J. (Menno) Prins – Professor in the department of Molecular Biosensors for Medical Diagnostics at the Technical University Eindhoven

Goal: Learn more about different sensor systems and evaluate our system.
Approach: We talked to Menno Prins, who himself is working mostly with enzyme sensors and immunosensors and involved him in a brainstorm session about applications for our sensor.
Results: Menno Prins could not tell us much about specific regulation involved in the use of biosensors, because he is not working with biosensors himself. However he could give us some useful advices about the possible application of our device. He advised us to focus on the mechanism within the cell. How can this be tuned to allow the cell to give a useful output? In other words: what biological readouts can we get? He was enthusiastic about the idea to allow the bacteria to produce and secrete medicines/pesticides as a reaction to pathogen-detection. However he also expressed concerns about the storage of these compounds within the cells. How are we going to make sure that our cell doesn’t degrade by itself and deposits its contents in the environment? Furthermore he advised us to extend our system by not solely focusing on the use of aptamers on the outside of the bacterial membrane. If another detection system provides more stability under certain circumstances, detection components can easily be modified to be used in our system. Finally he made us consider the option of using our system in a different cell. This could maybe help us overcome certain barriers imposed by law.

Q Fever

One of our application scenarios involves the use of bacteria in the detection of Q fever in domestic animals. Generally, people are quite enthusiastic that we are dealing with a local problem. However, to get an overview of the challenges within Q fever detection, we needed to talk to experts on this area. Therefore, we approached Anja Garritsen, who is a researcher from InnatOss, a research institute involved in the development of new detection methods for Q fever. We also talked to one of the farmers who had a Q fever infection on her farm who was very interested and involved in the development of new techniques to eradicate Q fever. Finally, we had contact with Q fever researchers from the University of Wageningen and GDdiergezondheid (the centre for animal health). An overview of these talks is presented below:

Dr. Anja Garritsen - Scientist working at InnatOss

Goal: Learn more about existing sensing methods that are used to detect Q fever.
Approach: We talked to Anja Garritsen, who is working at InnatOss and is greatly involved in the development of new techniques to detect Q fever. We asked her if she could tell us more about the systems they use. Also we asked her if she could see potential in the application of our sensor system. Thereby we asked her for advice on which molecules we could best use for detection.
Result: In InnatOss they make use of the detection of IFN-gamma for identification. She could tell us that this technique is only applicable after a person/animal has been infected with Q fever for 2 weeks already. Since the formation of antibodies is essential. Dr. Garritsen herself was very much interested in new techniques to detect acute prevalence of Q fever. This is currently only possible within the first 2 weeks of infection and requires the PCR of bacterial DNA. She could, however, also tell us that the development of new techniques is hindered by a reduction of the occurrences of acute infections. This makes it hard to study the development of particles in the blood that accompanies infection. When we asked her about particles that are prevalent after acute Q fever infection, she expected that Interleukin 2 and 10 and IFN-gamma might be the most readily available to detect. However these particles also occur in different bacterial infections and are therefore not specific.
Since we would like to use our device for the detection of particles associated with Q fever in milk of the animals, we further informed about the possibilities. Currently PCR-detection is used. Dr. Garritsen agreed that it is easier to get permission for the use of new treatment/detection methods in animals. Furthermore she could tell us that nearly everything that can be detected in the blood, can also be detected in the milk (including blood cells). She proposed to detect antibodies produced as a result of vaccination. By tracking the antibodies in milk we could determine whether goats are still sufficiently protected against Q fever. Thus our device could be used to track when new vaccination is needed. Finally we asked her general opinion about our device. She reasoned that if we could design a method that is easy in use and gives a quick output, there will be a market for many other veterinary and human diseases.
Jeanette van der Ven – Owner of a goat’s farm near Eindhoven and one of the board members of the ZLTO (association for entrepreneurs in the green sector)

Goal: Learn more about the viewpoints of a cattle-farmer when it comes to detection of diseases such as Q fever.
Approach: We contacted Jeanette van der Ven, who owns a farm where there has been an infection with Q fever and informed about her experiences with detection and treatment of Q fever so far. We asked her about her wishes, when it comes to disease-detection. And asked what she thought about our device.
Result: Mrs. Van der Ven explained that in her case it has been very hard to clarify that an Qfever infection had occurred on her farm. She told us that the rate of abortion rate on her farm rose, after which she got suspicious and sent several fetuses and placentas for examination. However only in the last case, several months later one could find traces of an Q fever infection. We asked mrs. Van der Ven what she thought about the application of our device for detection of Q fever in milk. Mrs. Van der Ven was very positive about the idea of having a toolkit that farmers can use themselves to check their cattle for diseases. She said there would be great interest from farmers for such early-warning systems. Thereby she also emphasized the need for detection-systems for chlamydia and salmonella in animals. Definitely the application in milk could be easy. However she was not completely convinced about the usage of antibody detection. She told us, some of the goats that she knows were infected with Q fever still score negative for an antibody-test. Thus she emphasized that a more reliable technique is needed for antibody-detection.
About the use of GMOs mrs. Van der Ven was quite open minded. She says: "As long as the environment, people and animal don’t suffer, there is no reason to be opposed of genetically engineered organisms." However she can imagine bigger steps can be made in the applications on cattle, than in humans. She predicts GMO’s in humans will be mostly used in prevention rather than treatment.
Dr. H.I.J. (Hendrik-Jan) Roest – Head of the department Bacteriology and TSEs of the Central Veterinary Institute (CVI) of the University of Wageningen

Goal: Learn about the general concepts of Q fever. What are the starting points for detecting Q fever? What are problems with the existing detection-methods.
Approach: Via the secretary of the Central Veterinary Institute, we were brought into contact with Dr. Roest. Dr. Roest is a veterinary microbiologist, who is strongly involved in research to Q fever. We asked Dr. Roest about current sensormethods and what problems he encountered using them.
Result: Dr. Roest provided us with information about some substantive questions about the detection of Q fever. Therefore he referred us to some interesting articles.
Dr. R. (René) van den Brom – Researcher working for the “Gezondheidsdienst voor Dieren” (a national institute that focusses on animal well-being)

Goal: Learn more about what the developments in the field of Q fever are and what the most commonly used detection methods are.
Approach: We were brought into contact with Dr. Van den Brom via HollandBio, a national institute that is involved in technical advancements in the field of biology. Dr. Brom works at an institute for animal well-being, where he is involved in research towards Q fever. We asked him some questions about the current status of Q fever research.
Result: Dr. Van den Brom also helped us to answer some of our questions about the development of Q fever, by handing us his thesis.

Detection of intestinal diseases

The application of our device inside the human body, might be one of the most controversial examples of possible usage. From earlier surveys (matchings days and wisdom of the crowds) however we learned that the general public is quite open-minded about the use of GMO’s in the intestines. There arguments mostly result in the statement: As long as the testing has been sufficient, and it is proven to be harmless and beneficial, than what is against the use of genetically modified organisms. In other words: They trust the expert. Therefore it was important to learn more about what experts thought about this application scenario. We contacted intestinal doctors, researchers, institutes and also people involved in regulation. The reactions we encountered were gently called disperse.

ICC (Initiative on Crohn and Colitis) – Gathering of intestinal doctors/researchers spread over the country that unite to fight inflammatory bowel diseases

Goal: Get feedback on the application of our device to use it for detection of intestinal diseases.
Approach: We had the great opportunity to join one of the meetings of the ICC, and present our idea to a board of intestinal doctors that were opinionated about the application of our device. The board shared their thoughts on our device and gave us suggestions for further development.
Result: The board could tell us that there are a lot of advancements in the field of research to inflammatory bowel diseases, such as Crohn and Colitis, but that the exact cause of these diseases remains unclear. Many different molecules (playing a role in inflammation) can be used to detect inflammatory bowel disease in the intestines. One of the most commonly used substances nowadays is Calprotectin. Furthermore the presence of certain compounds in the intestines can be used to judge the functionality of certain organs (e.g. elastase for pancreatic function). The ICC was very positive about the idea to create a device for home-usage. Thereby they emphasized that the device should be easy in use and cheap.
However, the doctors were hesitating to believe that DNA could be used as a source of protein-detection. They were very interested in the technique of using aptamers and found it surprising that a molecule with such limited variability in composition could be used for specific detection of molecules. Also they found the use of a bacteria in the intestine quite problematic. They confirmed that regulation is especially tight for the use of microorganisms in medicine. Any method making use of transcription factors will, according to them, by definition be rejected. Therefore they stimulated us to use a different scaffold for our detection-system, unless our device could produce a significant output. For that matter, they were quite interested in the idea of using the bacteria for specific drug-excretion. Thereby they emphasized that this could especially be useful in specific drug-targeting of tumors, by making use of tumor-specific proteins for detection.

Happy team members after a successful meeting!
Prof. dr. E. Dekker - Clinical researcher in gastrointestinal oncology at AMC-Amsterdam & Prof. dr. G.R. van den Brink - Basic researcher in gastroenterology, hepatology, oncology and immunology at AMC-Amsterdam

Goal: Get some insights from people working and doing research in the field of gastrointestinal oncology on the application of our device in the intestines.
Approach: We contacted two doctors from the gastrointestinal oncology department of the AMC-Amsterdam. Thereby we hoped to get their opinion about the usage of our device (making use of GMO’s) in the intestine. Also we asked them for suggestions to further exploit our idea.
Result: Both Prof. Dekker and Prof. Van den Brink were very enthusiastic about the idea of an easy-to-use device for cancer-screening. Thereby Prof. Dekker emphasized that she could see great benefits in the development of a test that can be used at home. This would not only decrease labour-intensity, as most test need to be performed in a lab. Also it would diminish the time a patient has to wait for his/her results. They engaged in a brain-storm session about potential target-molecules. They told us that nowadays human hemoglobin is mostly used to detect intestinal cancer. The presence of this substance indicates abnormalities, as normally no blood is to be expected in the intestines. The negative result of this test is very reliable. And a positive result requires follow-up research to make a distinction between intestinal cancer and other diseases like inflammatory diseases and haemorhoids. Another substance they considered to be useful for our research is CoxII-RNA. The presence of this substance in the intestines, indicates cancer.
For the detection of inflammatory bowel diseases, they suggested the use of Calprotectin. When we asked them if they thought our ideas were feasible, they were quite positive. Prof. van den Brink could tell us about research being performed to use bacteria for secretion of microbiological medicines in the intestines. Earlier one of these researches had been performed within their own group. Thereby they encountered one strict criteria, which was that the bacteria should be of the non-colonizing type. If the colonization of our bacteria could be restricted, than they could see great perspectives for the use of a system that interacts with a disease.

On our journey to Amsterdam
Prof. dr. J.P.H. Drenth – Head of the department Stomach-Colon and Liver diseases at the UMC- St. Radboud in Nijmegen

Goal: To get an idea of current intestinal detection methods and to get the opinion of an experienced doctor on the application of our device in the intestines.
Approach: Via different routes within the UMC – St. Radboud we were referred to prof. Drenth, to talk about the use of our system in the intestine. We asked prof. Drenth about current detection methods in the intestines. Also we presented our device and asked his opinion.
Result: Prof. Drenth saw potential in our idea, as he could tell us there are an endless amount of substances to be detected in the intestines. Some of them were mentioned by the other doctors we spoke as well, such as Calprotectine.
When we asked Prof. Drenth about the usefulness of our device, he was most enthusiastic about the idea of using it for real-time monitoring of intestinal cancer. He explained that nowadays check-ups involve the performance of macroscopic tests as colonoscopy, which brings great discomfort to the patient. If we could find a way to perform monitoring that is less invasive, that would bring great advantages.
Alexandra Daisy Ginsberg – Designer, Artist and Writer

Goal: Learn more about the thoughts behind a project where GMOs were proposed to be used inside the intestines. And inform about how Mrs. Ginsberg conveys her controversial design to the audience.
Approach: We contacted Alexandra Daisy Ginsberg about her design, inspired on the iGEM-project of Cambridge 2009. Thereby we asked her mainly about her thoughts on the use of GMOs inside the body. Also we informed what the reactions were to her project in which she and her fellow designer James King hypothetically introduced pigment-excreting bacteria in the intestines to colour egestions (the Scatalog).
Result: Mrs. Ginsberg explained to us that with her project she further wanted to provoke discussion about using GMOs in the body and that she was not necessarily taking a side.
Also she referred us to a similar research, where they modified gut-bacteria to remember signals it received from its environment. Thereby it forms a monitoring system of events occurring in the intestines. She hereby informed us that research, similar to ours, is already taking place and that her idea to use bacteria for diagnosis might not be far out of reach.

Pesticides

The application scenario that might have the biggest economic impact if it were to be realized, is the one where we would use our device for targeted pesticide secretion. This could however also be the scenario with the biggest implications for the environment. People we met at the RIVM-symposium were very enthusiastic about this idea. To further scrutinize the feasibility of this application we contacted people involved in regulation of the use of GMOs in the environment. Also we contacted one of the main institutes in the Netherlands involved in sustainable development of amongst others agriculture.

Dr. ir. F. van der Wilk – Executive director of COGEM, the Dutch institute that assesses applications for the usage of GMOs

Goal: Learn more about potential obstacles in the use of GMOs in the environment.
Approach: We talked to Dr. Van der Wilk, who works at COGEM (an institute involved in the assessment of GMO-applications). By posing questions we tried to get an understanding of what aspects of a design are important in the evaluation of the risk of GMO-usage.
Result: Dr. Van der Wilk could tell us more about specific requirements related to our application, since most of the forms that need to be adhered and filled out are quite standard and unspecific. Dr. Van der Wilk told us that environmental-risk analysis basically involves judging the impact factor. In other words: The chance of occurrence of an event times the environmental effect of this event. One of the aspects they value in their assessment is the strain of the bacteria that is used. Since we are making use of E. coli K12, this wouldn’t bring much of a hassle, as it is considered save. Another aspect is the specifity of the modification made: Is the effect of the modification specific for the target, or could it also interfere with other systems?
Furthermore it is of interest if the bacteria spreads. If so, you would need to consider the potential harm of the bacteria in the new environment. Thereby not only physical spreading of the bacteria is considered, but also the exchange of plasmids if modifications are not made in the main DNA-strand. And how long the bacteria can survive in the environment. It could therefore be interesting to look at safety-mechanisms to contain our bacteria, like the beads. However when we consider this solution we should also look at the potential risk of the bead being swallowed by some animal. Dr. Van der Wilk could not come up with research that overlaps ours. Thereby he assured that there is no fixed measure to assess the potential risk of GMO-applications. But certain consequences need to be considered and one needs to weigh the potential benefits against risks.