Human practices
Human practices
Find out how we connected our project to the wider world by integrating the needs and interests of multiple stakeholders
Introduction
Human Practices is an essential part of any iGEM project. It challenges engineers to make useful projects that contribute to society. Synthetic biology can bring innovative approaches to solve some major societal problems, however it can also raise many questions. This is where Human Practices comes in to make the teams more aware of the positive as well as the negative impact of their project. Our objective is to fully integrate all stakeholders involved into our project to end up with a therapy that will truly be a great benefit to as many people as possible.
Human Practices Page
On our Human Practices page you will find the work that we did for both Silver Human Practices and Integrated Human practices. The page will show you how we identified our stakeholders, considered their values, and implemented their needs into our project.
On the interactive timeline, you will see that we have met many people from different backgrounds and discussed our project with them at all stages. We used the Gibbs reflective cycle numerous times after the conversations with stakeholders to find out which direction we needed to go in with the project. More about this can be read on the interactive timeline.
Implementation Page
On our implementation page, you will read more about how we intend to bring cELPro into the world in the future. On this page, you can find the information about the improvements we still intend to make on our design, the market research we did, our businessplan, and how we intend to eventually make cELPro available to patients.
Silver Human Practices
In this section of the Human Practices page, the stakeholders that can give relevent feedback on our project, cELPro, are identified. Moreover, we analyzed their interest in the folowing values: safety and non-maleficence, public health, beneficence, justice, autonomy, profitability, innovation, and privacy. Click on the menu's below to read more about this.
As stated by the iGEM community: “Human Practices matters at every stage of your project”. With this thought in mind, the TU Eindhoven 2023 got inspired by the “syn-PNOIA Cycle” from the Patras Medicine 2022 team. This team from last year divided the iGEM journey into six chronological steps. A small adaptation of the “syn-PNOIA cycle” can be seen below.
The iGEM journey starts by defining and understanding the problem the team wants to tackle and ends with the proposed implementation into the real world. At every step, stakeholders are of great interest. Involvement with stakeholders helps to develop a project that is good and responsible for the world. However, not every stakeholder is equally useful at each step of the cycle. That is why the Human Practices team did a stakeholder identification to identify which stakeholders are of interest at which step. The results of the brainstorm session can be seen below.
After we discussed what stakeholders are of importance for our project at all five steps, we grouped all stakeholders into the six following categories:
- Science and research institutes
- Safety and ethics
- Health care and hospitals
- Laws and regulations
- Business and industry
- Public organizations and communities
We have to take into account that the stakeholders from the different categories described in the stakeholder identification section will have different interests. Furthermore, it is relevant for us to know what the focus is of the stakeholder, since in the end, they all need to be satisfied if we want to develop a successful product. To make the best design, the first step is to find out what the most important values are to our stakeholders.
We want to take a consumer-driven product design approach which has been proven to better fulfill the needs of the user than other methods[1]. This means that we will use value-sensitive design (VSD) to keep in mind and prioritize the values of our stakeholders, while also keeping track of the technological limitations of the design. This type of analysis has also been used by many other iGEM teams, such as those from TU Delft 2021 and TU Eindhoven 2022. However, we have given it our own spin.
VSD combines conceptual, empirical, and technical investigations[2]. This means that there needs to be a combination of stakeholder interviews, literature research, and a consideration of the technical limits of the product to find the best design eventually. This is not a step-by-step process but needs to be done over multiple iterative cycles to design a successful product. The process was perfectly described by Graubom et al. in 2017 and can be seen in the image below[2]:
The method helps our team to proactively consider the values of all stakeholders throughout the entire design process. For the stakeoldhers in the six stakeholder categories, we prioritized their values on a scale from 1-10, which we later on used to determine the direction that our project needed to go in. A rating of 1 means that the value is very unimportant to the stakeholder, while a 10 means that the value is extremely important to them. Moreover, it helped us to recognize conflicts between values and to prioritize which values should be integrated into our technology.
We recognized the following values and design requirements during our project. In the section below, you can find for each value how important we found the values to be per stakeholder group. A meeting with Zoë Robaey helped us to find out which values are the most important in medical ethics. The ratings are based on the conversations we had with the stakeholders from the group. More information about the conversations we had with our stakeholders can be read in our Interactive Timeline below. Also, more information about what the value means, how important it became in our design, and how we incorporated it into our project can be read at each value analysis:
Safety and non-maleficence
The most important value that was identified is safety, which is very closely related to non-maleficence[3]. Unsafe medication could cause harm or even death. The WHO (World Health Organization) has made a framework that contains all the important stakeholders and steps for safe medication. The Strategic Framework of the Global Patient Safety Challenge depicts the four domains of the Challenge: patients and the public, health care professionals, medicines and systems and practices of medication[4]. This framework shows that every stakeholder needs the final product and the production process to be safe from the production process up and until the treatment of the patient. This value has been a central part of conversations with many stakeholders from different sectors. We learned a lot about how to safely produce drugs via the GMP process from BioConnection. Furthermore, RIVM was able to tell us a lot more about the rules and regulations when it comes to bringing a therapy to market. Lastly, the doctors and technical experts we spoke to were able to point out some points in our design where safety could still use some improvements.
Some safety issues came up in our initial design that were addressed, such as horizontal gene transfer, where a plasmid might be taken up by another bacterium which could then start producing IL-10. An improvement of our design could be to move towards yeast in the future since we could then introduce introns in the plasmid, which will make other bacteria in the intestines unable to produce the protein. More information about this can be read on our Implemenation Page.
In another conversation about safety, Zoë pointed out to us that we are designing a vessel for drug delivery, and there needs to be control over who can decide what is incorporated into that vessel to make sure no harm can be done with our technology.
Our meeting with RIVM revealed that the time the bacteria stay alive after ingestion is very important to know. The strain on the environment will be much lower if our bacteria only stay alive a couple of hours after ingestion but if they remain alive for days, they might produce IL-10 in nature which can have negative effects. Furthermore, they advised us to investigate what happens when the patient takes too much of the medication, or does not even need it at all.
Public health
Public health is another value that cannot be compromised in the design of a product. The value Public Health is defined as people with good complete physical, mental, and social well-being and not merely the absence of disease or infirmity as stated by WHO[5]. Requirements for the value Public Health were explained to us by agencies such as RIVM, VIG, doctors, and patients.
To take the value public health into account, we have seen the need for our therapy to be scalable, so it will be accessible to the largest number of patients possible. Furthermore, biocontainment is an important requirement for public health as well. The living organisms that are ingested should not be able to survive outside of the body to reduce the chances of contamination. Additional research is needed to find out whether the organisms survive long enough in the intestines to come out alive. When this turns out to be the case, additional safety measures are needed. Lastly, the therapy should do no harm to the patient, which means that there should be no long-lasting side effects.
We learned from Peter from VIG that it would be very beneficial to public health if the bacteria we produce can be stored in better conditions than the current alternative biologicals, this could make therapies more accessible for people who live in places that are harder to reach.
Lastly, it is important to investigate whether the bacteria are still alive when they are passed from the intestines of the patient, because if they are alive in a sewage system, additional safety measurements might need to be taken.
Beneficence
The value beneficence requires that the procedure be provided with the intent of doing good for the patient involved[3]. Apart from that, we think that a new therapy will only be used by doctors and patients if it works better than the current accessible treatments. We analyzed together with experts and patients what points make our treatment more beneficial for patients than current treatments.
One of the greatest benefits for patients and doctors is that our treatment design does not require patients to visit the hospital often. They can collect their prescription at the pharmacy, instead of having to go to the hospital and undergo injections every 8 weeks. This will lessen the burden on hospitals and doctors and at the same time make the treatment less unpleasant for patients.
Justice
The value justice means that the burdens and benefits of new or experimental treatments must be distributed equally among all groups in society[3].
To ensure our technology can be accessed by all people who need it, we have tried to make sure our product can be produced easily on a larger scale. This is one of the reasons that we chose to work with bacteria. Furthermore, we have been in touch with a health insurance company to find out what requirements there are before treatments can become part of health insurance. Our goal for the future is to make our treatment affordable and part of health insurance for every patient who needs it.
Autonomy
Requires that the patient has autonomy of thought, intention, and action when making decisions regarding health care procedures[3]. Therefore, the decision-making process must be free of coercion or coaxing. In order for a patient to make a fully informed decision, they must understand all risks and benefits of the procedure and the likelihood of success.
To keep this value in mind, we need to make sure that we well-inform doctors who are going to administer the therapy, so that they can properly discuss the risks and benefits with their patients. Furthermore, the prescription information needs to be clearly written.
Profitability
For a product to be viable on the market, it needs to be profitable. This means that profitability can also never be overlooked when designing a therapy. For as many people as possible to have access to our product, it needs to be scalable, which will in turn also lower the production costs. We think that our solution is much more scalable compared to other alternatives such as cell therapy and that production is easier than the production of antibodies, since we do not need human cell lines.
This value is most important for the business and industry partners since if a company were arising from our project, or if another company should pick up our project, a profit needs to be made eventually. This means that the costs of production need to be significantly lower than what the customer is willing to pay for the product. To find out the costs of developing our project further, we talked to multiple experts, under which BioConnection, who do the fill and finish of drugs. They told us that the last production step of a small batch of our product will cost around 40,000 euros. Furthermore, Maikel Peppelenbosch has experience with running a clinical trial in research, he told us that a phase I clinical trial costs about 1,000,000 euros and that a phase II trial costs 10,000,000 euros. The numbers found in the literature were even higher[6].
At this stage of our project, however, profitability is not that important yet, since a good proof of concept is first needed. With that proof of concept, we want to look for intellectual property that we can use to file for a patent, which will help with profitability in the first years. However, we are aware that a patent cannot be granted anymore for anything disclosed in the iGEM competition. This means that first we need to optimize the product and find ways to patent the new parts. More about this can be read on our Implementation Page.
After this is achieved, the next step is to scale up the production process to where a high enough number of bacteria or yeast can be grown to make a product that can be distributed to many patients. The upscaling of bacterial growth has been applied before in the field of biomaterials for example and there is already literature that helps with how to scale up microbial processes[7][8]. More about upscaling and our business plan can be read in our Implementation Page.
Innovation
Innovation is a very important aspect of a project to lift off in the early phases. For stakeholders to be interested, they need to see clearly that the concept is new and promising for the future. This is mostly important for the stakeholders who play a role in the beginning, such as our university TU-Eindhoven.
Our design is innovative since there are no patents on the technology yet and the formation of an intracellular hydrogel is a very new concept, it has never been achieved before with a protein engineering approach.
Privacy
Privacy of patients should always be kept in mind when doing research on a new technology. This means that their data should be handled according to all regulations during clinical trials. This responsibility will lie mostly in the hands of the stakeholders who conduct the clinical trial, such as CHDR. We have conducted our own research amongst patients and the general public as well in the form of a survey and had to make sure to keep their privacy in mind. Before conducting the survey, we consulted the Ethical Review Committee of our own university.
Conclusion and Outlook
Stakeholders often have value interests that align with each other, however for some there might be conflicts. Safety and profitability are in conflict with each other, since making the production process safer often means that the production costs will rise as well. However, we think there cannot be a compromise on safety and that this is much more important than profitability. This is why profitability will only become important at a later stage of the development of the design.
As changes are made to the design, close contact with stakeholders will remain necessary to make sure that their most important needs are still met. And as soon as the values Safety, Beneficence, Public health, and Justice are well-incorporated in the design, it is possible to carry on with further animal and patient studies, and to perfect the production process to increase the profitability of cELPro.
Reflection
We discovered that for a project that is good and responsible for the world, you should always consider a balance between stakeholders and taking their values into account. It became apparent during the value-sensitive analysis that different stakeholders have different values leading to different design requirements. These design requirements can be in conflict and the goal is to meet the design requirements of all involved actors in such a way that the benefits for them are larger than the negative aspects. We tried to prioritize which stakeholders and values were the most important to try and keep most of them satisfied. This balance is something everybody in the iGEM community should keep in mind when they involve stakeholders in their project design. Future iGEM teams should not try to meet all design requirements, rather they should prioritize the requirements and try to satisfy the most relevant stakeholders first.
Integrated Human Practices
During our iGEM journey, we spoke to many stakeholders to get feedback on our project. Those stakeholders are divided into six categories: science and research institutes, business and industry, laws and regulations, safety and ethics, public organizations and communities, and healthcare and hospitals. More about the categories can be found below by clicking on the icons.
An overview of the conversations can be seen in the interactive timeline beneath. The tools that we used in this timeline are the optimized AREA framework of the iGEM team TU Eindhoven 2022 and the Gibbs Reflective Cycle. More about these tools can be found in the respective sections. Furthermore, please click the different stakeholder icons to learn more about them.
To integrate the feedback received from stakeholders it is important to close the engagement loop, different frameworks can be used for this. The AREA framework has been a commonly used framework among iGEM teams over the past few years. The TU Eindhoven 2022 team optimized this framework to the following four phases:
1. Purpose. In this section, the relevance and motivation of the conversation with the stakeholder in question is described.
2. Contribution. Here, the input of the stakeholder can be found, it summarizes the engagement and discussion we had.
3. Implementation. This section shows how we implemented the feedback and how it influences our vision.
4. Outlook. Here, the next steps are described that the team has to take to further improve our project.
The Human Practices work over the past months had an effect on our project on different levels. Moreover, it made us able to make motivated decisions. After these big changes, we reflected on the decision that we made using the Gibbs reflective cycle. An overview of the steps of the cycle can be seen below.
Interactive timeline
Click on each stakeholder to see how we implemented their feedback
February 17th
Prof. Dr. Ir. Luc Brunsveld
Prof. Dr. Maarten Merkx
Prof. Dr. Ir. Tom de Greef
Eindhoven University of Technology
PIs
In this first meeting with the PIs we discussed the first potential project ideas. Based on the conversation we decided to perform extensive literature research on ELPs (Elastin-Like Polypeptides).
February 23th
Prof. Dr. Willem Mulder
Dr. Roy van der Meel
Eindhoven University of Technology
Precision Medicine
In this meeting we discussed the potential project ideas that we already had and about the ongoing research in the precision medicine field. Based on the conversation we decided to focus on two potential projects: an ELP drug delivery system and cell therapy for a severe viral disease (due to confidentiality we are not allowed to tell which disease it concerns).
March 3rd
Prof. Dr. Ir. Jan van Hest
Eindhoven University of Technology
Polymer chemistry and biomedicine
The meeting with professor van Hest was used to learn more about ELPs and to give us some new ideas on how to work with it. After this meeting we need to choose between the two potential ideas that we have: a therapeutic hydrocell and a stem cell therapy for the severe viral disease.
March 20th
Prof. Dr. Ir. Luc Brunsveld
Prof. Dr. Maarten Merkx
Prof. Dr. Ir. Tom de Greef
Eindhoven University of Technology
PIs
In the second meeting with our PIs we presented two project ideas. After a discussion about the pros and cons of each project, we decided to continue with the project regarding a therapeutic hydrogel. The next step is to work out the project in more detail and to start talking with other stakeholders.
April 3rd
Natasa Marsic
The Gate
IP and patents
Natasa thinks that we have an idea that is patentable, but we need to consider the costs and time it will require.
April 10th
Diego Lopez Barreiro
Large Dutch chemical company
Modeling expert on ELPs
Diego explained to us how we can develop a molecular dynamics simulation to support our project. He provided us with a guide that has a step-by-step explanation of how to do molecular dynamics simulations.
April 11th
Paul van Zutphen
BioConnection
GMP on large scale
Paul told us to narrow down the scope of our project and think of what the production process may look like.
April 11th
Unknown employee
Medtronic
Med tech company
The employee from Medtronic advised us to narrow down our project so that we can find the right application.
April 12th
Prof. Dr. Ir. Luc Brunsveld
Prof. Dr. Maarten Merkx
Prof. Dr. Ir. Tom de Greef
Ir. Thijs van Veldhuisen
Postdoc. Eduardo Guisasola
Postdoc. Huynh Tien Duc Le
Eindhoven University of Technology
PIs and Lab supervisors
The supervisors gave us the necessary information to get started in the lab. Moreover, together we came up with the idea to use the intracellular hydrogelated cells as probiotics.
May 30th
Prof. Dr. Gijsje Koenderink
University of Technology Delft
Bionanoscience
Gijsje pointed out that is important to really get clear what the benefits of our technique are compared to other techniques such as nanoparticles.
June 8th
Drs. Monique Devillers
Erasmus MC
Physician-researcher stomach, intestine, and liver diseases (specialized in IBD)
Current treatments of IBD are often effective but are expensive and still give many side effects because they are not specific enough. For many patients there still is no suitable treatment.
June 16th
Paul van Zutphen
Dr. Alexander Willemse
BioConnection
GMP on large scale
Paul and Alexander made us aware of the potential strategies for the pill design for hydrocells, such as freeze-drying of the bacteria and a pH-sensitive coating. Furthermore, they told us more about the GMP process and its costs.
June 16th
Dr. Cheemeng Tan
Dr. Luis Eduardo Contreras Llano
University of California Davis
Synthetic Biology
We will probably still come across some technical challenges that we have to solve but overall, the stakeholders were excited about our initiative.
June 22nd
Dr. Gewnny Fuhler
Erasmus MC
Gastroenterology & Hepatology
Gwenny gave us her opinion about the molecular targets that we had selected until now. Before the meeting, we wanted to go for making an anti TNF-alpha antibody, however she pointed out that this might not be the best choice. We found out that we have to look into molecular targets again and that IL-10 and JAK/STAT inhibitors might be interesting.
July 6th
Prof. Dr. Maikel Peppelenbosch
Erasmus MC
Head of the laboratory Gastroenterology and Hepatology
Professor Peppelenbosch gave us an insight into his experiences of the phase 1 clinical trial he did with a bacterial therapy for IBD excreting interleukin 10. Moreover, he gave us his critical opinion on our project and gave new advice on how to make the platform safer.
July 20th
Dr. Zoë Robaey
Wageningen University
Ethics of GMOs
Keep in mind the four principles of medical ethics in your design and think of who will get to decide what the bacteria can produce.
July 24th
Dr. ir. Céclile van der Vlught-Bergmans
Dr. Mirjam Schuijff
RIVM
Safety of Biotechnology & Safe-by-Design
With Cécile and Mirjam we spoke about the risk assessment that is done for every new medicine, they gave us an overview about what components of our project need to be confirmed to be safe for human use. However, they were positive about the concept and saw a new method to potentially treat a variety of diseases.
August 16th
Jos van der Wijst
BG Legal
Intellectual property for tech startup/scale-up companies
With Jos, we spoke about the possible IP strategies of cELPro. Although the iGEM competition is open source, he advised us to always have something in reserve to protect the technology.
August 20th
General members of the public
We asked several people, ranging in age and education level, about their opinions of the use of GMOs as a treatment. Even though the public thought there would be a contrast in opinions based on the educational level, there was no significant difference.
August 25th
IBD patients
Crohn & Colitis NL
In July, we contacted the Dutch Crohn’s & Colitis Foundation and asked them if it would be possible to share a survey on their social media. This was done to find out what the impact of IBD is on patient’s life, and how IBD patients would feel about cELPro. They kindly agreed, and posted the survey on their social media in August. In the span of a few days, we got nearly 200 responses from IBD patients.
August 29th
Peter Bertens
VIG
Microbiologist who is occupied with laws and regulations for innovative medicine
With Peter, we discussed what steps are required for a new type of drug to be approved. Furthermore, we talked about the laws and regulations for GMOs.
September 19th
Anonymous
Health insurance company
Advisor
The health insurance employee told us about when medications are covered by insurance, when patients have to pay, and where to find the cost of all medications in The Netherlands.
September 19th
Patient 1
The patient told us about the impact of IBD on her life. She said that aside from the pain, what makes it really difficult is mostly the fact that everything needs to be carefully thought about and planned. She said that most of the medication causes extreme fatigue and starts working less overtime. She thinks a new medicine that is suitable for longer or permanent use where the quality of daily life would still be reasonable would be most valuable.
September 20th
Patient 2
The patient told us about the negative impact of IBD on her life, since several treatments did not work or lost effectiveness over time. When comparing medications she used over the past years compared to cELPro, she saw potential in cELPro as a new treatment since it responds to the deficiencies of current treatments.
All year long
Bart van Grevenhof
The gate/ Eindhoven University of Technology
Business Developer Student Entrepreneurship
Bart helped us multiple times during our project to advise us on making the best possible sales pitch. Moreover, he helped us develop a solid business plan.
Purpose
During our iGEM journey, we can get the help of three PIs. The expertise of the PIs are chemical biology, protein engineering, and synthetic biology. In the first few weeks as an iGEM team, we learned about synthetic biology and brainstormed about a potential project. After a few brainstorming sessions, we had 5 global project ideas that we wanted to discuss with the PIs and hear their opinion about.
Contribution
During the meeting, we discussed the project ideas that we had. They were enthusiastic about our Elastin-Like Polypeptide (ELP) idea for therapeutics but thought other ideas (e.g., related to Parkinson’s disease) were too difficult for us in the timeframe we have.
They advised us to do two things. The first thing they suggested was to perform more literature research about topics that had some potential. Secondly, they advised talking to other professors and researchers at the Eindhoven University of Technology (TU/e) to discuss our existing project ideas and potentially get other ideas from them since they have slightly different expertise.
Implementation
After the conversation with the PIs, we had the feeling that the ideas that contained ELPs had the most potential. We decided to put our focus on this idea for the next few days.
Outlook
The next step is to do more in-depth research on ELPs and plan meetings with other professors and researchers.
Purpose
After the meeting with the PIs, we planned a meeting with Willem and Roy. Both of them are specialized in precision medicine, therefore they use a lot of synthetic biology. We wanted to propose the same 5 potential project ideas as we did to the PIs and learn more about the current research in this field.
Contribution
As opposed to the PIs they were less enthusiastic about the idea considered ELPs since there has already been done a lot in drug delivery by previous teams, and it is not that innovative. The conversation about the ongoing research in their field gave new insight that led to a potential idea.
Implementation
Nevertheless, the opinions about ELPs were divided, and we still wanted to keep this idea. Moreover, the team got very enthusiastic about the new idea. We decided to let go of the other four ideas and do further literature research on these two ideas.
Outlook
The next step is to learn more about ELPs by planning a conversation with Prof. Dr. Ir. Jan van Hest. His research group is currently working with these proteins. Thereafter, for the new idea we need to do extra literature studies.
Purpose
Since Professor van Hest is working on ELPs, we wanted to propose our idea of using these proteins to him. The goal was to see how viable our idea was and to get feedback to potentially improve it.
Contribution
We were provided with several strategies for how to implement and execute the idea we had regarding the ELPs. In addition, the professor provided other ideas of how these proteins could be employed for an application in synthetic biology, we could for example express the proteins in bacteria.
Implementation
The meeting gave us a better understanding of what the possible applications of ELPs could be. However, an important thing to take into consideration was still how to implement it as a therapy.
Outlook
The next step is to make a decision between the two projects we have in mind based on different aspects. If we use ELPs, the best thing for us to do is to meet with the people actually working with ELPs in the lab currently, in order to see what they think of the ideas and if they are willing to help us develop them.
Purpose
After the meetings with other professors from the TU/e, we had two concrete project ideas that we wanted to discuss with our PIs. The first idea was to create therapeutic bacteria with an intracellular hydrogel using ELPs and the other was a stem cell therapy for a viral disease.
Contribution
The PIs were enthusiastic about both ideas. Together with them, we decided to weigh up the pros and cons of each project related to potential supervision and guidance in the laboratory, the impact we can make, the synthetic biology part, the costs, and the feasibility of the project.
The impact of the therapeutic bacteria would rely on the application. However, the project would be impressive, since working with ELPs to create intracellular hydrogelated cells is already a new concept. Despite that working with these proteins is quite new, there are a few researchers in the group of Jan van Hest at the TU/e who work with them and are willing to guide us during the upcoming months. In addition, working with bacteria is not very expensive since they are easy to clone.
Stem cell therapy would make a huge impact. However, we saw some problems regarding working with (infected) human cells and the level of synthetic biology. Besides, with this project we do not really incorporate new elements, we just put them together. This would increase the feasibility of the project also in comparison with the hydrocells, but it would be less innovative. In addition, the costs when working with human cells are higher than when working with bacteria. Another disadvantage of this project is that there was no guidance possible in the laboratory.
From these points, we concluded that the hydrogelated bacteria with ELPs project is more suitable than the project regarding stem cell therapy.
Implementation
We were very happy with the meeting since we had the feeling that we made a very motivated choice on which project we continue with. We now know where to focus on and what the next steps are.
Outlook
Since we now know what the core of our project will be, we can start thinking about how to start in the lab and discuss this further with the lab supervisors. We can also start thinking about other stakeholders and experts suiting our project that can help us find the right application by telling us more about the current problems and needs.
Purpose
We wanted to find out if someone with experience thinks we could file for a patent and if she thinks that our idea is creative and new. We also wanted to know more about the process of filing a patent so we could start thinking if we wanted to apply for one ourselves.
Contribution
Natasa told us that there are multiple types of patents, and told us that doing a Dutch application would be best and that this would cost around 4,000 dollars. Regarding the timeline, she told us that we can file before the iGEM competition, but that the actual application will take longer than the timespan we have until the competition. Furthermore, she advised us to use an non-disclosure agreement (NDA) with any partner who we would be discussing technical details with. She would send us the example of the NDA that is used within the TU/e. For filing the patent, she told us that we would need initial lab results to show that our idea works and that we would need to get clear who should be listed as the inventors and the owners of the patent.
Implementation
We discussed the results of this meeting with our PIs, who all have a lot of experience with patents already as well. They mentioned to us that an application will take a lot of time and that, considering the time pressure we are under and the small team we have, it would not be a good idea to go forward with this. They also pointed out that a patent is not needed for the iGEM competition and that the application could interfere with how much we could enclose during the competition and that this will make getting sponsors and partners a lot harder. We have come up with different ways to keep our unfair advantage compared to other competitors, which you can read on our Implementation Page.
Purpose
We wanted to get feedback on our general idea and find out the point of view of an industry expert. We wanted to gain knowledge about which hurdles we need to tackle if we want to make our project a viable product in the future. BioConnection has lots of experience with working with GMP and doing their processes on a large scale.
Contribution
During the meeting, Paul mentioned multiple hurdles that we still needed to tackle. He pointed out to us how important it is to think about how we want to package and administer our bacteria. He also questioned us why this drug delivery system would be better than other systems that are being developed (nanoparticles as drug delivery systems for example). He also told us to really narrow down on one specific disease.
Implementation
After our meeting with Paul, we thought of reasons why our system would be better than most drug delivery systems and the reasons we came up with were: our platform is very robust, easy to modify, and we can grow the bacteria quite easily since they are easier to produce than nanoparticles. Furthermore, we can trigger the release of the drug by building in triggers in the bacteria in the future. We also made an appointment to meet him at BioConnection on the 16th of June to see the GMP process in practice.
Outlook
The next step for us was to talk to more medical professionals to find the best disease for us to target. We also needed to do more literature research about this topic.
Contribution
The expert asked if we had already thought of our technology having applications in fecal transplants and mentioned that it might be interesting to look at. She also mentioned that sym4bio might be an interesting company for us to have a look at to help us with our modeling work. She also recommended us to reach out to a GI doctor and narrow down our scope to 1-2 diseases.
Implementation
We considered the idea of fecal transplants, however we saw no application of our bacteria that are unable to divide. We thought that for fecal transplants, one of the required characteristics of the bacteria should be that they can divide so that they can stay in the bowel for extended periods. This is why we decided not to go this route
Outlook
The next step for us was to find physicians with knowledge about different bowel diseases.
Purpose
Since we made a decision to carry on with the project regarding therapeutic hydrocells from bacteria with the use of ELPs, we wanted to speak with everyone who contributed to the project. This meeting is meant to discuss some details of possible strategies for ELP expression in E. coli, hydrogel formation, and characterization.
Contribution
During the meeting, we discussed some details of the lab work, especially how to crosslink the ELPs for the hydrogel formation. After a while, the topic changed to the application of hydrocells. The past few weeks we all focused on a therapeutic application probably in the form of an injection. However, the PIs warned us about criticism if our idea is to inject bacteria into humans. Therefore, they gave us the idea to use it as probiotics.
Implementation
The feedback on our idea of how to work with ELPs in the lab was very useful. The supervisors gave us enough information so that we could start making constructs of the plasmids that we would work with. In addition, the meeting changed our view of the application of hydrocells. We want to look further into the options to let it function as a probiotic by doing literature research and talking to experts from the industry.
Outlook
The next steps are to start making constructs for the lab, do more literature research on the application, and talk to experts from the industry to find the right application fitting the current problems and needs.
Purpose
We wanted to tell Gijsje more about our iGEM team and our project. We showed her the different options that we were exploring when it comes to choosing the disease that we wanted to make a therapeutic for.
Contribution
Gijsje asked us some very good questions, such as which genes were involved and why we wanted to use the specific molecular targets that we showed her. Furthermore, she asked us what the benefit of our technique is, compared to the use of nanoparticles for example. Lastly, she asked us how we wanted to trigger the drug release in the intestines. Overall she was very enthusiastic about our project and wished us good luck in the rest of our project.
Implementation
The need to think about the benefits of our technique became very clear to us and this is something we picked up and started to think about as soon as possible. Also, since Gijsje was most enthusiastic about the use in the treatment of IBD, we decided that we wanted to talk to a doctor who specialized in IBD.
Outlook
The next step for us was to contact a doctor who specialized in IBD to get a better idea about the current treatment shortcomings and the costs of current treatments.
Purpose
We wanted to get the general opinion of Monique when it comes to our project and to find out if she believes that the application that we have in mind could really help patients in the future. We also wanted to gain more insight into the current treatment options and their shortcomings and costs.
Contribution
Monique told us more about the current treatments for IBD. She said that Prednisone is often used to treat acute flair-ups and severe cases. However, this drug is not suitable for long-term treatment. When the acute phase seems to be under control, a switch is made to aminoacylates, but these are not effective for all patients and can lose their effect over time. When they do not work well enough, a switch is made towards biologicals, where anti-TNF antibodies are usually the first choice because they are less expensive (about four to ten thousand euros per patient per year) and very effective. When these antibodies do not work, there are more options for antibody use. However, these cost about 40,000 euros per patient per year and there are more downsides to the use of these antibodies. More about this can be read on our Project Description Page.
If patients are prescribed a type of biological, they need to visit the hospital for an injection every 8 weeks, or they need to inject themselves every 2 weeks, which is undesirable for many patients. Furthermore, even though these drugs are effective, they are still not specific and patients experience many side effects because they target molecules that are key players in the whole immune system. This is why patients also get slightly elevated chances of cancer.
Monique pointed out to us that our idea at least needs to be effective, give much fewer side effects, or be much less expensive than the current options to ever become a part of the treatment plan for IBD.
Implementation
It would be a good idea to look again into the molecular targets that we could use to see if there were any more specific targets that would in turn result in fewer side effects. For this, Monique offered to get us in contact with someone from the clinical lab at the Erasmus MC.
Outlook
The next step for us was to schedule a meeting with the expert on the lab at the Erasmus MC. To find out more about appropriate molecular targets. Furthermore, we realized it would be a good idea to figure out what the costs would be for the production of our product in the future.
Purpose
Two months earlier we had our first contact with Paul, who gave us some really useful feedback and criticism on our project. Based on the mutual interest in Paul and our team and the positive vibe during the first conversation, Paul decided to invite us to BioConnection. Here, we wanted to learn more about the GMP process on a large scale, but also to get some new feedback on our project and some knowledge about the options for how we could 'pack’ our hydrocell into a pill.
Contribution
Paul and Alexander were again very enthusiastic about our project and the innovative component it has. For the pill design, we discussed a few strategies. One of the most potential options was freeze-drying the hydrocells. This method dehydrates the bacteria, making it suitable for long-term preservation. The bacteria can be re-activated at body temperature. More about how we plan to integrate this into the design of cELPro in the future can be read on our Implementation Page. To ensure that the hydrocells do not become active before they arrive at the right place in the body, a pH-sensitive coating can be added. In this way, the bacteria are only released once they are in the right place where they can immediately start performing their function.
In addition to these useful tips for the pill design, they gave us a good idea about the costs to produce a 2L batch of our product. This will cost around 30-40k euros.
Implementation
The conversation we had with Paul and Alexander showed us the potential options for the pill design. The pill design is one of the most important components of the implementation of our project in the real world.
Outlook
The next step is to further design the packing of the cells. Hereby, we have to know more about the freeze-drying process and potential coatings. First, we want to do a short literature study before we contact experts.
Purpose
Having been inspired by a paper written by the researchers of UC Davis (intracellular hydrogelated cells with PEG-polymers), we wanted to see if we could replicate some of the experiments they did to characterize their bacteria. However, after reading the paper, there were still some unanswered questions which we wanted to ask the authors. They were happy to have a meeting with us to further discuss technical details and answer our questions about where they see these types of cells go in the future.
Contribution
They were able to tell us things like under which conditions their bacteria were able to survive and for what periods of time. This was useful information for our lab experiments. We also asked them what they think would be the benefit of using bacteria over other forms of therapy, like nanoparticles. The key benefit is that this is an active system and is able to do chemotaxis for example. Furthermore, they can carry a much higher payload as opposed to nanoparticles. Bacteria can also be ideal if you have a pathway that cannot be easily replicated in a nanoparticle. For example, when a therapeutic needs to be delivered but cannot be put into a nanoparticle.
Prof. Tan also told us about a few challenges that we might encounter along the way. It is harder for us to control the hydrogel formation inside our cells compared to their system. Furthermore, he mentioned that the survival of the bacteria might not turn out to be better than we expected because some processes in the bacteria are hindered by the formation of the gel. However, he was also not completely sure if this was the case.
Implementation
We now know that we need to try to have as much control as possible over the expression of our ELPs inside the bacteria since this is not only important for the gelation, but also for the overall functioning of the cells. We also knew more about the potential applications that our cells might get in the future.
Outlook
Our next step is to get our first results from the lab. Based on these results we can adjust our strategy.
Purpose
The purpose of this meeting was to find out if we had a good idea about suitable molecular targets that we could use a therapeutic on. We wanted to know more about more specific molecular targets that we had not thought of yet and we also wanted to find out if there were methods to make sure the treatment would stay more local in the intestine.
Contribution
At the beginning of the meeting, Lisa and Merel showed Gwenny some of the molecular targets that we had in mind and we were most enthusiastic about the use of an anti-TNF nanobody. However, Gwenny pointed out that the Fc part of the anti-TNF antibody plays an important role in its mechanism, and that therefore the nanobody would probably not work as well as we would expect. Other targets we talked about were IL-6, IL17, IL12, and IL23. She mentioned that it has been tried to target IL-6 and IL-17 for IBD, but that these results were not promising. Anti IL-12 and IL-23 agents are being tested in combination and seem to have some effect.
She also told us that there are some general negative effects of antibodies. Over time, the patient might start to develop antibodies against the administered drugs, which will cause a loss of their effect. Furthermore, they always need to be administered in a systemic way which causes a lot of side effects, because in reality, these drugs are effective but not specific. The only drugs that work specifically in the bowel at the moment are 5-ASAs, all other medication is systemic.
Gwenny told us that there was interesting research years ago about IL-10 and that JAK/STAT inhibitors are gaining popularity and that there are already some in the clinic. She said that these might be some interesting targets to look into and mentioned that she could also connect us with someone who did research about IL-10 for the use of IBD treatment before. He also used transgenic bacteria to deliver the therapy, so his experiences could be very helpful to us.
Implementation
We started doing more research into IL-10 and JAK/STAT inhibitors for the treatment of IBD and we let go of the idea of using anti-TNF nanobodies.
Outlook
The next step was to discuss with the team and supervisors whether we would go for IL-10 or a JAK/STAT inhibitor. This choice also influences whether we need to express more proteins or incorporate some parts where we can chemically link a small molecule.
Purpose
During the last meeting we had with Gwenny from the Erasmus MC, she told us to look into IL-10 as a potential anti-inflammatory therapy. Professor Peppelenbosch, who is the head of the laboratory Gastroenterology and Hepatology, did in 2006 a phase 1 clinical trial with bacteria that expressed IL-10 to treat IBD. Since this is very similar to our project, we wanted to learn more about his research, the difficulties associated with GMOs, and why his research has stopped.
Contribution
First, we spoke more generally about IBD and the problems of current treatments. Professor Peppelenbosch advised us to focus on Crohn's disease since this is a bigger clinical problem than Colitis ulcerosa. The majority of the treatments for IBD are administered intravenously. To administer a treatment orally, there are some obstacles to overcome, such as gastric acid and bile. To solve this problem, multiple medicines are surrounded by a coating that can pass these liquids. In the research from Professor Peppelenbosch, they freeze-dried the bacteria and surrounded them with multiple pH-dependent coatings.
Before his research, there was already some research done about IL-10. It was shown that IL-10 has great potential to have an anti-inflammation function when it is administered locally. However, when administered systematically and in high doses, it has a reverse effect, this can be avoided by the use of bacteria. Even though the research was well thought out and the treatment had a positive effect on sick patients, there were some issues. These issues were concerning safety, ethics, and costs. In 2006 the world knew way less about GMOs, therefore there were a lot of negative opinions. Moreover, people were scared by the idea of taking in bacteria. Professor Peppelenbosch thought our idea was very beautiful, since the technique is safer and the control rate is higher. The costs were another issue of his research. To do a phase 1 clinical trial the right way, you need to spend approximately 1M euros, whereas a phase 2 clinical trial costs even 10M euros.
Even though Professor Peppelenbosch saw great potential in our project, we spoke about how to make the platform even safer. In his research, they used thymidine-dependent bacteria, so they did not use antibiotics. However, this dependency can be transferred via homolog recombination. That is why he advised us to look into the literature about yeasts as a host instead of E. coli. More about this can be read on our Implementation Page
Implementation
Professor Peppelenbosch confirmed that we have a well-justified project that could make a real impact on IBD patients. He was enthusiastic about the idea of using IL-10 as a biological therapy, which made us also very enthusiastic. Moreover, he gave us an insight into how clinical research and trials work, what problems you face, and an indication of the price which is very useful for the implementation of our project.
Outlook
The next step is to further look into the safety and ethics of GMOs. We would like to talk about this with one of the co-researchers of Professor Peppelenbosch. Moreover, we should talk to our supervisors to see if they agree to choose IL-10 as the biological therapy. If everyone agrees, we could finally complete our project.
Purpose
We wanted to have a meeting with Zoë, who we met at the Dutch iGEM meet (more about this can be read on the Education & Communication Page.), to discuss more about the ethical considerations that are important for the design of our project. Furthermore, we wanted to know more about the ethics of using GMOs in general and Zoë already has a lot of experience with iGEM, so we wanted to know more about which things are important to keep in mind when it comes to Human Practices in the iGEM competition. Lastly, we were wondering if she saw ways that people could misuse our technology.
Contribution
Zoë told us more about the four principles of medical ethics. Non-maleficence, beneficence, justice, and autonomy were topics that we discussed. We also discussed that it is important to consider who will have access to our technology, not only who can be treated with it, but also who gets to decide which drugs and substances can be produced with our bacteria. We also mentioned how we have a hard time thinking of what consequences our technology could have for society, and Zoë advised us to make comparisons to other technologies in the biotech industries and look at what is applicable to our project. She also told us it might be a good idea to talk to an insurance company to find out how we can make our therapy accessible to as many patients as possible.
Implementation
We have implemented the advice Zoë has given us in our value-sensitive analysis and design and reached out to a health insurance company.
Outlook
Zoë gave us some literature to read about the topics that we have discussed. In the upcoming week, we want to read those papers to implement them in our value-sensitive analysis.
Purpose
RIVM, the Dutch National Institute for Public Health and the Environment, strives for a healthy people living in a safe and healthy environment. The institute analyzes medicines and gives scientific advice about the preparation, quality, and the use of it. We wanted to speak to Cécile and Mirjam to talk about possible safety issues regarding our project. Moreover, we wanted to know a bit more about the steps that needed to be taken to go from the laboratory to eventual animal studies and clinical trials.
Contribution
The first thing that Cécile and Mirjam clarified is that every new medicine needed to be assessed for environmental risk for human use. Questions where we need to think of are for example what happens if the living bacteria ends up in the sewer? Are the bacteria able to exchange its DNA with other organisms? The fact that the bacteria with the hydrogel inside cannot divide is an important fact for the risk assessment since this increases the viability. However, the formation of the hydrogel is temperature dependent and also in some conditions reversible. Since we do not know the lifespan of the bacteria, it is possible that the bacteria will again be able to divide when it leaves the human body. This makes the chance of risks higher. A solution for this could be a kill switch before the bacteria will be excreted or using bacteria with a short lifespan such as lactic acid bacteria. More about this can be read on our Implementation Page.
Another question they had was what would happen if the bacteria fell apart inside the human body. We know from studies at our university that ELPs are non-immunogenetic, so they will not form a problem. However, we need to check if other components of the bacteria could form immune responses. To answer this question we have to keep in mind that in people with IBD, the intestinal wall is more leaky.
In addition, they were very clear that we have to do more research on IL-10. We know from the meeting with Maikel from Erasmus MC that it works anti-inflammatory when administered locally, but the other way around when administered systematically. This is important for the safety of the dose and effect. However, we do not know what the effect is on people who don’t have IBD. Moreover, what is its effect when released in nature? These are things we want to touch upon in the future, more about it can be read in our Outlook.
The last thing we spoke about was how to upscale our project to possible other studies. They taught us that is extremely important to build a file during the evolution of the concept in the lab. You also have to think beforehand about what methods will be necessary to confirm that the concept is safe for people. Eventually, the treatment needs to be tested on humans. Before it will be accepted on the market, which costs around 8 to 10 years, you need very specific data such as the effectiveness of treating the specific disease. The new treatment needs to be as effective or even more than the already existing medication or it needs to be way cheaper for the patient.
Implementation
Overall, Cécile and Mirjam thought positively about our project. They were honest that we need to take some steps to ensure that the treatment will be safe to use, so they told us we need to check how a risk assessment is done and what questions will be asked. The meeting gave us a good overview of what to do further research on and opened our eyes to possible problems that we had not thought of before.
Outlook
The further steps that need to be taken are to do more (literature) research on the potential risks of our bacteria and IL-10 regarding environmental risks and people without IBD and checking the application form of the risk assessment of new medicines.
Purpose
BG Legal is a full-service law firm, where Jos is a lawyer for innovative companies in the technology- of life sciences/pharma sector. He specializes in IP law, patent law, and IT law. The purpose of the contact with Jos is to learn more about our options for a patent at this stage of our project or even after the competition. Moreover, we wanted to know a bit more about the rules regarding the pharma industry.
Contribution
The first and most important thing that Jos said is that at the time of a patent application, the invention should be new and thus not publicly published. If you do choose to make the invention publicly available, the technique should not be reproducible for others. A few months ago, we had a meeting with Natasa from the Gate. She thought our technology was very patentable, however, our PIs discommended applying for it at the moment. Since the iGEM competition is open source, it would be very difficult to get a patent afterward. Making our technology public ensures that others cannot apply for a patent either. This would allow us to turn it into a start-up at a later stage. Although this is a good method to protect the patentable aspect of the technology, Jos advised us to always hold some cards.
Moreover, we spoke about our competitors who are doing something similar. More about our competitors can be found on the Implementation Page. We wanted to know when you are in conflict with an approved patent application. According to Jos, the claims in the patent are the most important. If our technology is not in conflict with those claims, there will be no problem. He advised us to do a patent search on Espacenet.
In addition, we had a brief conversation about the rules and regulations when working with body materials, participants during clinical trials, and marketing. Jos did not know all the ins and outs but gave us some websites where we could find more information about these aspects.
Implementation
The conversation with Jos gave us an insight into the possibilities of taking cELPro to the next level, even without a patent. More about IP can be found on the Implementation Page of our project.
Outlook
Jos mentioned that it is important that the project is not in conflict with approved patents. Therefore, the next is to do a patent search on Espacenet.
Purpose
Since we are developing an orally ingested treatment for IBD using GMOs we wanted to know the opinion of the general public about the use of this and related types of treatment.
Contribution
We asked a small group of people, ranging from 17 to 55 years old, to fill in the following survey:
What do you think about when you hear the term genetically modified organism or engineered machine? And where have you learned that knowledge?
If they don’t know, explain what GMOs are
How willing are you, on a scale of 1-10, to use a treatment containing engineered machines in the following ways:
A. The engineered machine is injected
B. The engineered machine is orally ingested
C. The engineered machine is applied to the skin
D. The engineered machine is in a medical device
Please elaborate.
Do you think there might be a difference in opinion on GMO-related concerns between the public and academic institutions or the public and public sector bodies? If so, Why?
Results
A big part of the group could explain in relatively simple language what GMOs are, for example they know that it has to do something with adjusting DNA.
The results of the second question can be seen in the Figure below.
It can be seen that people are least enthusiastic about injecting GMOs as a treatment. Whereas, they are equally willing to apply it on the skin and to use GMOs in a medical device. Our approach, an orally ingestible treatment, scores in between. A part of the group based their judgment on the opinion that an injection is the most invasive while something on the skin or a medical device is the least invasive. The other group is willing to use everything when it is safe and helps for the disease it’s treating.
Despite the range in educational level, all people gave the same type of answer to the last question; everyone thinks that the opinion of the academic community is different compared to the general public because the academic community has more knowledge, a different perspective, and a better understanding. Remarkable is that this cannot be seen in the results of the second question.
Implementation
We noticed that the general public is open to new treatments as long as they are safe, effective, and as less invasive as possible. cELPro matches those three important points, this confirms that we have focused on the right things.
Outlook
Since we noticed that the general public knows the basics of GMOs, but not the underlying parts of it, we now know that we have made the right decision about where to focus on with our educational activities. More about this on our Education & Communication Page. .Purpose
In July, we contacted the Dutch Crohn’s & Colitis Foundation and asked them if it would be possible to share a survey on their social media. This was done to find out what the impact of IBD is on a patient’s life, and how IBD patients would feel about cELPro. They kindly agreed, and posted the survey on their social media in August (the post can be seen on our Education & Communication Page). In the span of a few days, we got nearly 200 responses from IBD patients.
Results
From the results, it became clear that most patients are medicated and have had several different therapies in the past. On a scale of 1-10, there was a clear peak at ‘7’ when asked how much trouble the patients experience daily from their condition. When asked to elaborate, what was striking, was that most patients said they felt extreme fatigue and an extreme lack of energy daily. Below, some of the results can be found in graphics.
Implementation
Overall, the survey gave us some insight into patients' medical history, how much IBD affects their daily life, and how they would feel about new treatments, such as cELPro. This insight has been used for the part about ‘end users’ for the Implementation of cELPro.
Outlook
To get some more in-depth answers, we will take it a step further and personally reach out to a few patients to have a meeting with them. Hopefully, that way, we will find out even more about the impact of IBD on their life and how they would feel about cELPro.
Purpose
VIG is an association that helps pharma companies with the development of innovative drugs. They do not produce any products but have conversations with the government when laws might need to be changed for new drugs and they advise pharmaceutical companies.
Contribution
When we pitched our project to Peter, he found it an innovative approach. However, he did tell us that it is very important to make sure we can convince others that cELPro is safe and that the coating we use for our pill needs to be one that is already available on the market, otherwise expensive approval procedures are needed.
Next, we talked about our target patient group. Peter mentioned that innovative treatments like this do not usually enter the market for all patients to use straight away. He said that a good start would be a patient group where other treatments are unsuccessful to prove in this group that the therapy is safe and that it works better than other alternatives. Peter mentioned that another interesting target group could be patients who live in places that are hard to reach. Often, antibodies are not available in developing countries because they cannot be shipped or stored for long enough under the right conditions. If the storage conditions and shelf life are much better than for current alternatives, then this could be an interesting target group. We have implemented this in our business plan which can be found on our Implementation Page.
The next discussion we had was about the process of clinical trials and how to eventually get cELPro on the market. Peter told us that we need to find a hospital with a license to work with GMOs who are willing to do a phase I clinical trial with cELPro on healthy individuals. A phase I trial will give us a lot of data about whether the bacteria die in the bowel or are released into the environment and whether the therapy is safe. This data is crucial for the next steps. When we move forward to a phase II clinical trial, it is important to find out what metrics can be used to determine the severity of the IBD symptoms that the patient experiences, ideally this would be something we can measure in the blood or stools. This study needs to prove that the therapy is safe and effective. We wrote more about this on our Implementation Page.
Lastly, we discussed the timeline of bringing a drug on the market. Peter mentioned that it usually takes ten to twelve years to bring a new drug to the market. Most of this time will be put into development and clinical trials. He also told us that most companies start upscaling their production about two years before the drug enters the market.
Implementation
We have gained great insights into what our target group should be at the beginning when cELPro enters the market. Furthermore, we have gotten a much better idea about the timeline of bringing drugs to the market, which will influence our business plan and implementation section.
Outlook
There will be a second meeting with Peter where he will answer all of our questions and we can go into even more detail. We will also use the information Peter gave us in our business plan.
Purpose
The purpose of the meeting was to find out how long it takes for new medications to get added to health insurance, whether there are any requirements for this, and when people have to pay a personal fee for it.
Contribution
The employee told us that the requirements for new medications are set by the government, so she did not have an answer to that question. However, she did tell us that all health insurance companies have a list of preferred medications. For this, they look at the different brands with the same active substances and usually go for the least expensive medication. Preferent medications are fully covered by insurance and other medications will not be given out by the pharmacy unless you have a clear doctor’s referral. In that case, though, it will not be fully covered by insurance. Some medications cannot ever be covered by insurance. The Dutch government has a database on which can be found how expensive medications are and whether they are covered by insurance or not. The Dutch Healthcare Authority has a big influence on this.
Outlook
The meeting provided us with new information and gave us more insight into how health insurance companies work.
Purpose
We wanted to know more about the impact of IBD on the life of a patient. Moreover, a patient can give another type of feedback on our project compared to a doctor or scientist.
Contribution
The patient told us that she was only diagnosed last year with Crohn’s, but doctors think she might have had it for about 15 years. The diagnosis came late because she was already taking anti-inflammatory medication for another disease. She also said that the impact of IBD really depended on the flare-ups, but she is way more tired compared to before and cannot work as many hours. She also cannot work out or go for a walk as often and is less inclined to go on holidays, because she has to carefully think everything through and make sure she is always near a toilet. That, combined with the pain and fatigue, makes the disease very restrictive for her.
The patient tried different medications, but those did not work that well. She then switched to immunosuppressors but had an allergic reaction to them. She is now trying biological therapy. However, she mentioned that all of those treatment options work systemically, which has really affected her immune system.
When asked for feedback about cELPro, she said that she thinks it would be very valuable to have another option before having to get surgery. She thinks it would also be great if it does not work systemically so that it won’t affect the immune system as much. Additionally, she said that she thinks it would be most useful if there was some routine for taking the pill so that there is no risk of starting too late or forgetting it.
Implementation
The conversation with this patient confirms that current treatment options aren’t great and that there is a need for a platform like cELPro that will not completely affect the immune system. More about this can be found on the implementation page.
Outlook
Overall, the patient is satisfied with cELPro and thinks it would be a good option for a new treatment option to treat IBD.
Purpose
We wanted to know more about the impact of IBD on the life of a patient. Moreover, a patient can give another type of feedback on our project compared to a doctor or scientist.
Contribution
The patient told us that she was diagnosed in her teenage years. IBD has made her life very challenging since one of the symptoms is that you needs to go to the bathroom all day. Moreover, she has tried almost all current treatments, but those did not work or lost effectiveness over time. Eventually, this led to surgical removal of the intestine.
In addition, she thought that current treatments are quite harsh. She experienced many side effects when using different medications. When using medication that is administered by infusion, she needed to visit the hospital every 6 to 8 weeks, which is not very optimal. However, other medication, such as a lancing device, needed to be stored in the fridge and used every day.
She was convinced that cELPro could be a good alternative to current treatments. The most important difference to her is the fact that it works locally compared to the systematic approach of most treatments. However, in the ideal world, there would be a treatment that does not work as a disease control but heals IBD.
Implementation
The conversation with this patient confirms that we developed a platform that takes the wishes of patients into account, they think it is comfortable. More about this can be found on the implementation page.
Outlook
Overall, the patient is satisfied with cELPro and thinks it would be a good option for a new treatment option to treat IBD.
Purpose
We had a hard time getting started with our simulation. We spoke to a large Dutch company that works with ELPs who recommended that we contact Diego since he did some simulations for them. We were hoping Diego could tell us what is possible when it comes to ELP simulations to get us started.
Contribution
At first, we were expecting that it would be possible to simulate whether we would see gelation or not at different temperatures. However, we soon found out that even a simulation expert like Diego has not been able to simulate this well yet. He explained more about the model that he made for the large Dutch company.
We had to adjust our expectations for the molecular model that we would want to make. Together, we came up with the idea of simulating two molecules and see if they interact or not at different temperatures. He recommended us to use NAMD software since it is relatively easy to work with and complete software. He also said we could use a course-grained model and simplify it to reduce the computational time.
Diego gave us a step-by-step plan to make a molecular dynamics simulation, it can be found here: Guide for molecular dynamics.
Implementation
We started following the guide of Diego, this became the starting point of our modeling. More about this can be read on our Simulation Page.
Outlook
The next steps were to do more literature research about he simulation and how to get it working.
Purpose
Bart is active at our university and The Gate as a business developer. He has much experience in the business world and knows how to speak to different types of audiences. With his expertise, he could help us develop a business plan suiting our project. Moreover, he is able to advise us on how to tell our story in the best way possible.
Contribution
During our iGEM journey, we had different presentation opportunities. However, we noticed that is quite difficult to adapt our story to the type of audience, especially when they do not have an academic background. Bart advised us to remove all difficult words from our pitch and think about the similarities we have with the public. In addition, he listened multiple times to our pitches and gave feedback.
Since Bart knows a lot about entrepreneurship, he inspired us with his knowledge of how to write a business plan. He let us think about the necessary steps that need to be taken after the project, even though he has no background in synthetic biology or healthcare. His feedback on the first versions of our business plan took it to the next level.
Implementation
We implemented all of Bart his feedback into our storytelling, presentations, and business model. At the moment we are very pleased with the end result of the business plan, and we are grateful for Bart’s feedback. The business plan can be seen on our Implementation Page.
Outlook
Now it is time to really discover if Bart his tips & tricks for presentations have worked since we have to present our project at the Grand Jamboree!
Reflection 1 - Choosing research topic
Description
In the first month of our iGEM project, we started with doing wide-ranging literature research, brainstorming with the team, and meetings with our PIs and professors of the Eindhoven University of Technology to decide on which research direction we want to focus on for the iGEM competition. The challenge was to find a project which is innovative, original, feasible, and realistic.
Feelings
All team members were enthusiastic about the potential project topics. We were all very excited to conduct research on these topics and to learn more about the (technical) details. However, it felt like a very difficult decision since it determined the foundation of the project.
Evaluation
To make a well-considered choice, we spoke multiple times to our PIs and other professors. Moreover, we divided our team into two subgroups. Each group did its own literature search and presented its findings during a team meeting. This helped us a lot to gain more information about different issues in a short time period. Eventually, we discussed the pros and cons and our opinion of the topics together with the PIs to determine the most potential project.
Conclusions
After the last discussion with the PIs, we concluded that the engineered bacteria to create therapeutic hydrocells would be the most innovative and feasible project for the iGEM competition. In addition, since the university has expertise on this topic, we are able to get good supervision in the laboratory.
Action plan
Our next step is to decide which disease we would like to target. From the literature search we already did, we thought about immunotherapy for a specific type of cancer. To make a decision we are planning to do more literature research and later to talk to experts.
Reflection 2 - Change in treatment class
Description
During previous team- and subgroup meetings, we mainly focused on a therapy that is intravenously administered. However, our PIs indicated that some people would look very critically at injecting bacteria into the bloodstream. According to them, we could better focus on a type of probiotic that has a function in the digestive tract. This should result in less criticism, because of the presence of the human microbiome in the digestive tract which consists among other things of bacteria.
Feelings
Even though we agreed with the feedback from the PIs, it felt like a setback that we had to start doing literature research over again. However, the change in the therapeutical direction gave us more belief in our project since we were a bit insecure about it.
Evaluation
After doing some literature research, we found that probiotics are a very potent topic. Multiple big companies in the food industry such as Campina and Danone are developing probiotics for health benefits. However, we thought that using probiotics as a therapy is not as much developed since living, dividing bacteria has multiple disadvantages. Therefore, our technique would be a great opportunity.
Conclusions
After the meeting with our PIs, the brainstorming sessions, and the literature search we concluded that using our hydrocells to target a disease in the digestive tract would be the best choice for our project.
Action plan
The next step is to start talking to experts in the medical field, such as doctors, who know which diseases are currently untreatable or have invasive therapies. These diseases are potential clinical pictures that can be treated with our technique.
Reflection 3 - Choosing the application
Description
A few weeks ago we made the decision to change the treatment class we will be focusing on; diseases in the digestive tract. In the past weeks, we have done literature studies on possible applications. Thereby, we found celiac disease and inflammatory bowel disease (IBD), which are both very interesting and relevant clinical pictures. After the conversations we had with Gijsje and Monique, we decided to fully focus on IBD as the application of hydrocells.
Feelings
The decision to focus on IBD felt like a real milestone since we have been working towards this point since the beginning of the project. Moreover, we all felt really good about this application since we already mentioned that different people in the surrounding suffer from IBD, making it very relevant.
Evaluation
It took a while to make a decision on the application of our project. We would have liked it if this could have been done earlier in the project since it made us all a bit worried that we did not have the right application yet. However, it was not necessary to make the decision earlier since we needed to start in the lab with the formation of the hydrogel and not the application. In addition, in this way we made our decision based on the discussion we had with relevant and specialized people making it more substantiated.
Conclusions
Based on the literature studies and the conversations we had, we decided to focus on IBD as the application of hydrocells. The current treatments are very expensive, lack some sort of specificity, or have very strong side effects which can be solved with the platform we are designing.
Action plan
The next step is to further look into the underlying science of IBD and the possible molecular targets. We will again do this with an extensive literature study and also by discussing it with experts.
Reflection 4 - Choosing the biological therapy, IL-10
Description
Since we have decided to use cELPro to treat IBD, we have searched a lot of literature for potential biological therapy. Before we spoke to the stakeholders, we had a very extensive list of molecular targets. After the meetings, we narrowed down the list and after a brief discussion with our supervisors and PIs we concluded that IL-10 would be the best biological therapy.
Feelings
The literature search made us feel a bit overwhelmed since there is so much literature on molecular targets. Therefore, we especially felt really happy after the meetings with Gwenny and Maikel, both working for Erasmus MC, they gave us a really good insight into what is already known and what could or could not work.
Evaluation
Even though it is very sensible to do a literature search before a meeting with stakeholders, they can tell us more in half an hour than what we could find after a whole day of reading literature. For the next time, we will do a less extensive literature study, but a quick search so that we are still prepared.
Conclusions
With the decision to focus on IL-10 as the biological therapy for cELPro, our project is finally complete.
Action plan
In the final period of the project, we will focus on expressing IL-10. But before we can express IL-10 in the hydrocells, we need to do a literature study on it, order the DNA sequence, and discuss with our supervisors about the best approach.
Reflection 5 - The end of our iGEM journey
Description
We have reached the end phase of our iGEM journey. To determine whether our project, cELPro, is good and responsible for the world we tried to involve as many stakeholders as possible during every stage of the project. We spoke to around 20 stakeholders from different categories such as safety and ethics and business and industry. By involving many stakeholders from different fields, we got feedback on all aspects of our project. Moreover, with the combination of engaging with the stakeholders and performing a value-sensitive analysis, we integrated their values into the design of cELPro.
Feelings
We are very proud of what we have accomplished in a relatively short time span and that we managed to take the feedback from the stakeholders into account. However, we had the ambition to engage with several other stakeholders, but we did not get in touch with them.
Evaluation
At the beginning of the journey, we started with a brainstorming session where we identified all relevant stakeholders. With the stakeholders in mind, we made a plan on how to determine whether our project is good and responsible for the world. We integrated the feedback we got into the design of cELPro by validating the feedback with other stakeholders and literature.
The Human Practices and Implementation wiki page displays all the Human Practices work we did. We made use of several frameworks such as stakeholder identification, value-sensitive analysis, a timeline where we used the adapted AREA framework from the iGEM TU-Eindhoven 2022 team, and the Gibbs reflective cycle. With those frameworks, we build on the work from previous iGEM teams, but we also contributed to it from our side which other teams can build upon in the next years.
Conclusions
The Human Practices work was not only essential to determine whether our project was good and responsible for the world, but it was also essential for its design. Together with our stakeholders, we have created a project that we are very proud of.
Action plan
We hope that everything that we have done so far will be helpful for other researchers and teams in the future.
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Science and research institutes
Experts from science and reserach institutes have a good view on developing new technologies. Mainly, they can help us with defining and designing a good solution.
Healthcare and hospitals
Stakeholders that belong to this category are experts from the healthcare sector. They are either working with patients or on new medication. They can help us defining and understanding the problem, verifying the need, and defining a good solution.
Safety and ethics
Stakeholders from the safety and ethics field let us think about the principles of our project. Their input is especially valuable when designing a solution and for the proposed implementation.
Laws and regulations
Experts from this sector are specialized in either intellectual property or the development of innovative medicines. They can advise us when designing a solution and for the proposed implementation.
Business and industry
Stakeholders that belong to the business and industry category have experience with the market. Their feedback is valuable when defining and designing our solution and for the proposed implementation.
Public organizations and communities
Everyone who does not belong in the other five categories belongs to this one. They are either patients, an IBD foundation, or the general public. Depending on their background (i.e., patient or the general public) they can help us with defining and understanding the problem, verifying the need, and the proposed implementation.