Purpose

We spent the first weeks as new members of the iGEM community learning about the ins and outs of the iGEM competition and synthetic biology. From this, we learned that synthetic biology could be applied much broader than only to therapeutics and diagnostics. It could also be applied to topics such as energy, environment, or manufacturing. Nevertheless, based on the expertise of our PIs and the interests of the team members, we decided that the tracks therapeutics or diagnostics should be the focus of attention during the first project brainstorming sessions. In preparation for these brainstorming sessions, we looked into project topics of previous iGEM teams, considered current research performed at our university, and analyzed the state-of-the-art research of synthetic biology. From these sessions, we came up with 8 potential project ideas ranging from an innovative BRET (bioluminescence resonance energy transfer) sensor to an exosomal miRNA detection system, and to a sensing platform for long-covid based on a synthetic receptor. The goal of the first meeting with our PIs Prof. Dr. Ir. Luc Brunsveld, Prof. Dr. Maarten Merkx, and Prof. Dr. Ir. Tom de Greef is to discuss all potential options and find out which ideas are both technologically achievable and have the potential to be good and responsible for the world.

Contribution

During this first meeting, the PIs made clear that some project ideas such as a BRET sensor, were focused too much on protein engineering or organic chemistry rather than synthetic biology. In addition, an idea based on inducing dimerization of two proteins in a cell as a potential treatment platform was thought to be too ambitious for the time and resources that were available to us. They advised us to do three things. First of all, they suggested that we should narrow down our project ideas to only 2 or 3 and perform a more in-depth literature study on these topics. Secondly, they stressed we should always search for the link with synthetic biology. Finally, they advised us to take into account the expertise available within Eindhoven University of Technology (TU/e) and its research groups. This way, we can have valuable discussions and proper guidance during our project.

Implementation

Based on the conversation with our PIs, we decided to focus on three topics that were clearly based on synthetic biology. The three topics include the GEMS-based system (Generalized Extracellular Molecule Sensor platform), the exosomal miRNA diagnostic tool, and a design that stimulates bacterial cell death as an alternative to antibiotics.

Outlook

The next step is to do further research into these three project ideas. We decided to split up into smaller teams of 2 to 3 people per subject to do efficient literature studies. Thereafter, we will present our findings to the other group members. During the literature study, we will take several things into account. First, we will try to build upon or combine previous iGEM achievements. Also, we put a high value on innovativeness while the idea should still be technically feasible. Lastly, we will aim for a project that has a positive influence on the world and vice versa.

Purpose

Currently, our team is performing a literature study on the three chosen project topics: the GEMS (Generalized Extracellular Molecule Sensor platform) system, exosomal miRNA as a diagnostic tool, and a design that stimulates bacterial cell death as an alternative for antibiotics. For each topic, we investigated the state-of-the-art of the technology, its application, and what the corresponding proof of concept could be. In addition, we investigated if previous iGEM teams did something similar. All information retrieved from the literature was discussed within the team. However, we also wanted feedback from the professors to hear their opinions. Therefore, the goal of this second PI meeting is to discuss the three topics more in-depth with our PIs Prof. Dr. Maarten Merkx, Prof. Dr. Ir. Luc Brunsveld, Prof. Dr. Ir. Tom de Greef, and our instructor PostDoc Alexander Gräwe. Secondly, we would like to get feedback on the feasibility and originality of each concept.

Contribution

In general, the PIs clarified that it is plausible if the project has overlap with previous iGEM projects. This would be beneficial if our project could improve upon previous work. Essentially, we should find the unique selling point of our project, the thing that makes us different. In addition, we should investigate whether related previous projects had promising results, to get a sense of the feasibility of the project.

The PIs were hesitant about the topic regarding the miRNAs. Since there is only a little experience with miRNA at our university, we could not get much help from them. Regarding the concept that serves as an alternative to antibiotics, they mentioned that it was not the most innovative one of the three ideas. Therefore, if we wanted to focus on that topic, we should find good selling points. The PIs were enthusiastic about the GEMS system as a potential therapeutic for autoimmune diseases. They confirmed our suggestion that we could use the GEMS system to generate decoy receptors to treat autoimmune diseases. According to the PIs, the benefits of this concept include the experience of the GEMS system at our university and the feasible modeling opportunity. To conclude, the PIs were most enthusiastic about the GEMS system as a treatment for autoimmune diseases.

Implementation

After the meeting with the PIs, we reviewed their feedback with our team. We discussed the pros and cons that were given for each topic. In addition, we assessed several aspects of each idea; we investigated the feasibility and originality of the project idea, and we looked into research conducted at our university and/or by previous iGEM teams on the respective topic. Lastly, we considered the support and expertise available at our university for each idea.

Outlook

Based on the advice of the PIs and the discussion with our team, the next step is to choose a project topic. With this choice, we would reach our first milestone. After a project topic is chosen, we must delve deeper into the topic by performing extensive literature studies, followed by reaching out to experts that can help us throughout the project.

Purpose

To obtain feedback on the feasibility and desirability of the concept and design of our freshly chosen project; cell therapy !MPACT to treat the autoimmune disease MS, we arranged a meeting with a medical immunologist and associate professor Henny Otten, associate professor Jorg Loosdregt, and full professor Femke van Wijk. These experts work at the Center for Translational Immunology (CTI) department of the Utrecht University Medical Center (Utrecht UMC). These experts are very closely interconnected to the clinic, while at the same time being scientifically grounded. This enables them to both reflect on the feasibility and desirability of the GEMS-based therapy platform. Therefore, the goal of this meeting is to create an open atmosphere in which we obtain a flow of new insights to improve our project design. We will pitch our project idea and continue with a brainstorming session, in which we want to receive feedback on how to improve our proof of concept design, and how to make it technologically feasible. Furthermore, the desirability from a clinical and patient point of view needs to be validated.

Contribution

To start with, the experts of Utrecht UMC were very enthusiastic about the innovativeness of our design and they recognized the potential of the technology. Besides that, the experts gave us insight into the needs of clinicians. They noticed some important benefits of our cell therapy, compared to current treatments used for many auto-immune diseases. For example, most current immunosuppressive drugs are non-specific and have many side effects while our cell-therapy-based design with a “decoy” receptor aims to react to a specific auto-immune disease. Moreover, they explained that our cell-based therapy could act much faster upon flare-ups of the disease. With this, possible relapses of the autoimmune disease could be prevented. However, they also had some critical notes concerning the design. To obtain a working and viable therapy, it was stressed that the autoantibodies associated with the autoimmune disease should be pathogenic and thus fluctuate with the course of the disease. In addition, associate professor Loosdregt emphasized that decoy receptors could potentially aggravate autoantibody production due to a positive feedback loop. As a solution, they unanimously advised us to use Interleukin 10 (IL-10) excretion as an output of our engineered cell rather than decoy receptors. IL-10 lacks the positive feedback loop and is anti-inflammatory. Lastly, they advised us to focus on an autoimmune disease that not only is characterized by pathogenic autoantibodies that represent disease activity but also has a high morbidity rate and poor current treatment methods. This would enhance the desirability of our treatment for the clinic. The experts suggested considering dermatomyositis as a target disease.

Implementation

The meeting with the experts of Utrecht UMC helped us to understand the best possible application of !MPACT. In our team, we discussed the feedback that we received. We decided to look into the suggestions given by the experts;

1. Consider other autoimmune diseases that are more feasible for our project

2. Implement IL-10 as the output of the engineered cells, instead of decoy receptors.

Outlook

Our next step, thus, is to delve into other, more feasible, autoimmune diseases for our project. In addition, we will explore the suggestion of using IL-10 as the output of the engineered cells. Furthermore, we are aiming to gain more feedback on the feasibility and desirability of our project design from other experts in this field. Since we also participate in the TU/e contest (Communication), we also plan to reason our project from an entrepreneurial point of view. For this, we reckon that it would be extremely useful to discuss our cell therapy with a pharmaceutical company, to evaluate its business opportunity.

Purpose

To verify the desirability and feasibility, and to assess the viability of our project we aimed to meet with a clinical chemist. Dr. Joyce Curvers is a clinical chemist at the Catharina hospital and has expertise in autoimmune diseases. Because of the process of choosing a disease for our therapy !MPACT went quite slow and not flawless, and since the people from UMC Utrecht had doubts about MS (multiple sclerosis) as our target disease, we wanted to gain input regarding a good, suitable autoimmune disease. Joyce Curves has much knowledge about different autoimmune diseases, their biomarkers, and their current treatments. Therefore, we want to brainstorm about possible autoimmune diseases for our cell therapy with Joyce Curvers.

Contribution

Joyce Curvers suggested several autoimmune diseases with proper disease markers. Her first suggestion was vasculitis, an autoimmune disease with well-known autoantibodies against the proteins MPO and PR3. Another proposition was lupus nephritis, which is characterized by a single-stranded DNA marker. The third suggestion was systemic sclerosis, however since this is an irreversible disease, this was probably less suitable for our treatment.

Joyce Curvers indicated that autoimmune diseases are often caused by apoptotic bodies that are not completely removed by the body. Targeting specific markers on the apoptotic bodies and thereby catching these apoptotic bodies would be even better than catching autoantibodies. Then, the origin of the disease could be targeted. Finally, Joyce Curvers suggested that we should talk to more UMCs and expert centers as they have much knowledge about autoimmune diseases and can give us input regarding choosing the right application of our therapy. This would help us prioritize the right values in our project.

Implementation

Based on the input from Joyce Curvers we performed research on other autoimmune diseases, considering her suggestions. In addition, we discussed our current design of !MPACT that catches autoantibodies using ‘decoy’ receptors. We decided that we should keep our concept simple, keeping in mind what is feasible within the timespan of the iGEM competition. Therefore, we determined that targeting and removing apoptotic bodies would be too ambiguous for our project. However, the potential of curing an autoimmune disease by targeting apoptotic bodies could be interesting for the outlook of our project.

Outlook

The next step is to reach out to other University Medical Centers to discuss our project with them, get input about a suitable disease, and evaluate the values of our project. We certainly will contact Maastricht UMC and Erasmus MC, since Joyce Curvers gave us some names of people that we could contact. Next, to UMCs we also aim to include pharmaceutical companies to discuss the business case of our project.

Purpose

In the previous conversations with Dr. Joyce Curvers of the Catharina Hospital and the immunologists from the Utrecht UMC, we were advised to look into other diseases for our cell therapy rather than MS. Moreover, they emphasized that our concept with the “decoy” receptors would not be technologically feasible. To get a second opinion on these critical notes, we decided to talk with the experts of Novartis. Rick Henderik, CSO of Novartis in the Netherlands, and Hidde Douna are experts in medical development and have much experience in pharmacy research. Mark van Hattum has a lot of experience in sales, marketing, business, and healthcare relations.

Contribution

Novartis immediately advised us not to apply our cell therapy to MS for multiple reasons. First of all, the autoantibodies of MS are patient-specific and thus vary extremely between patients. This means that we should design multiple receptors onto our cells that target different autoantibodies for each patient specifically, which would not be feasible. Secondly, many institutes and companies are doing research for improved treatments against MS. This means that there are many competitors. In addition, when using the concept of decoy receptors, you need to have a disease where the autoantibodies are causing the disease. For MS this is not the case, because its autoantibodies are not pathogenic. They also disproved our suggestion to apply our cell therapy on Long-Covid, since there is not much evidence for autoantibodies involved in Long-Covid yet. Furthermore, they advised us to think about the current treatments of the autoimmune disease we aim to choose as the target for our cell therapy !MPACT. To be able to add value to the standard of care, our new treatment should have significant advantages compared to current treatments.

Concerning the technology of our cell therapy, Hidde Douna agreed with the idea of Utrecht UMC to change the output of our cell from “decoy” receptors into IL-10. To suppress inflammation, this would be more feasible. Moreover, we received an important take-home message to take into account: They urged us to think about the complete implementation process of a cell therapy ranging from the R&D phase to bringing therapy on the market. This can have huge implications on the design of the therapy. Concerning this, Novartis offered guidance for the development of a business plan.

Implementation

From multiple stakeholders, we received advice to change both the disease target and the output of our cell therapy. The stakeholders taught us to consider multiple aspects when choosing an appropriate disease as a target for our cell therapy: current treatments of the autoimmune disease, the function of the autoantibodies, prevalence of the disease, severity/morbidity of the disease, and clinical manifestations. Based on the obtained feedback, we decided to critically reflect on our cell therapy design and its application. We tried to find supporting literature for the judgments of the experts, to make well-considered decisions for our project design. Moreover, we started to look both into the implementation of our cell therapy and the development of a business plan.

Outlook

Our next step is to plan a crucial meeting with the team, in which we have to decide the target disease for our cell therapy again. This decision must be made based on the literature study and the feedback obtained from the experts we approached. Next to this, we will delve deeper into the implementation of our cell therapy and its business viability. To boost this process, we aim to contact even more (pharmaceutical) companies.

Purpose

The BOM (Brabantse Ontwikkelings Maatschappij) is a company that supports innovation and entrepreneurship. To obtain insights on the feasibility of our project design from a point of view other than University Medical Centers and pharmaceutical companies, we planned a meeting with the BOM. The BOM could advise us on the implementation of !MPACT.

Contribution

The BOM was enthusiastic about our project and its innovative character. However, they expressed a few concerns regarding the feasibility of getting the therapy to the market. First of all, they mentioned that cell-based therapies are not without risks. For example, it could lead to side effects or an immune response against the injected !MPACT cells could arise.

Using HEK293T cells in the human body would presumably trigger an immune reaction. Retrieving cells from the patients themselves to subsequently engineer them to obtain the receptor would be a safer approach to prevent the repulsion of the cells by the immune system. Moreover, they were hesitant about the effectiveness of the ‘decoy’ receptors. The concerns that arose involved whether the decoy receptors would be capable of capturing enough autoantibodies to reduce their concentration in the blood and whether enough decoy receptors could be placed on the cellular membrane to be able to capture enough autoantibodies.

Implementation

The feedback regarding the possible immune reaction caused by using HEK293T cells, triggered us to think about which cells should be engineered and implemented in our cell therapy. Retrieving cells from patients and engineering them with our receptors would result in a more viable therapy. In addition, because of the risks of cell therapies, we were urged to critically review whether dermatomyositis would be suitable to treat with a radical treatment. !MPACT should, thus, be applied to autoimmune diseases that cannot be treated effectively yet. Furthermore, since BOM also expressed concerns regarding the decoy receptors as the output of our engineered cells, we critically reflected this output of our engineered cells, using the findings from literature and the feedback obtained by the expert meetings.

Outlook

The next step is to decide what output we should implement in our engineered cells. In addition, we will discuss the disease dermatomyositis we aim to treat with stakeholders, including UMCs and hospitals.

Purpose

After some time working on our iGEM project, we started to think about our business model and the viability of our project. For instance, we questioned ourselves, what should be the next steps regarding entrepreneurship, who are our ideal customers we should target, and what would be the ideal revenue stream. Contacting a company like ThermoFisher Scientific could help us to validate our business model and bring our experimental design and every aspect that comes along with it to reality. ThermoFisher Scientific has a wide variety of (medical) products. Therefore, it is an interesting company to discuss our business model with. In this meeting, we will talk about product marketing and our business model with Hana Schlorová, Sacha Massop, and Marc Storms. Marc Storms is expert in life science product marketing.

Contribution

In this meeting, we learned that it is essential to quantify the actual gain for our primary customers: pharmaceutical companies. We also learned that we should specify what our cost structure consists of and what financial gains we can expect. After the meeting, they sent us some additional information about the return on investment; a crucially important parameter to various pharmaceutical companies which we should incorporate into our business plan.

Implementation

After the meeting with ThermoFisher Scientific, we learned how to improve our business plan. Based on the informative documents that ThermoFisher Scientific sent us after the meeting, we elaborated on approximated costs and savings. These documents explained clearly what business quantifications are essential for a successful business model. Also, we calculated the return on investment, which showed us the actual timespan in which our project would be profitable for an investor. With this, we were able to quantify our business plan in more detail.

Outlook

Upon the adjustments to the business model, the next step is to validate whether our approximations such as the return of investment, costs, savings, etc., are in the right order of size.

Purpose

After the previous meeting with ThermoFisher Scientific, we tried to quantify our business plan. However, we found it difficult to make assumptions about the complete cost structure of the business plan. Organon has experts in the field of pharmaceutical process engineering and business development. Therefore, the experts from Organon could teach us about the production process of medicine, which we could apply to our engineered cell therapy. Production costs and efficiency are vital to the business viability of new medicine. Moreover, the production process including the quality controls is indispensable if you want to produce a safe and responsible cell therapy. Therefore, the goal of the introductory meeting with Organon was to gain information on the production process of medicine and its costs. We also aim to learn how we can apply the information about the production process to our cell therapy.

Contribution

Organon was enthusiastic about our engineered cell therapy, but they missed the implementation of the therapy. For them, it was not clear what the production cycle of the engineered cell would look like and how this would affect the treatment from a patient’s point of view. Moreover, they missed the next steps beyond the lab. They remarked that it is already crucial to think about all steps of medicine development in the early design phase of !MPACT since these can have an essential impact on the design of our cell therapy. These steps are for example the production process, clinical trials, marketing, market authorization, etc. Therefore, Organon had two pieces of advice for our team. Firstly, they encouraged us to contact cell therapy manufacturers, such as KitePharma, BMS, or Johnson & Johnson, to gain more information on the specific production process and quality controls necessary for cell therapies. Secondly, they suggested that we should investigate the complete process of cell therapy development which ranges from the design of our cell therapy to the phase of marketing. Based on the drug development phases we could make a much better estimation of the cost structure.

Implementation

Based on the advice we received from Organon, we tried to contact all three cell therapy manufacturers for an interview with an expert on the production process and its safety measures. Secondly, we started to think about the next drug development stages. For this purpose, we consulted literature to find specifics of these stages concerning ATMPs (Advanced Therapy Medicinal Products) under which cell therapies are categorized.

Outlook

The next step is to plan meetings with the cell manufacturing companies to learn about the production process of cell therapies. Also, we have to plan a follow-up meeting with Organon to discuss our business plan with their business department to assess the commercial viability of our cell therapy. The meeting with Organon triggered us to critically think in a broader sense concerning implementing safety in our project. Therefore, we plan to consult more stakeholders to discuss safety during the entire drug development process.

Purpose

After we gained information from the previous meeting with Dr. Joyce Curvers and meetings with UMC Utrecht, BOM, and Novartis, we decided to develop a cell therapy to treat the autoimmune disease dermatomyositis. Dermatomyositis can be divided into several subgroups, including MDA5-positive dermatomyositis. This is a well-defined subgroup of dermatomyositis, as specific autoantibodies, called anti-MDA5 antibodies, are present. Therefore, for the proof of concept of our cell therapy, we decided to engineer our cells with a GEMS (Generalized extracellular molecule sensor) receptor that can bind these anti-MDA5 antibodies if a patient has dermatomyositis. This binding would subsequently result in the excretion of interleukin 10 (IL-10) by the cells to suppress the autoimmune reaction. The purpose of this meeting with dr. Joyce Curvers from the Catharina Hospital Eindhoven was to get feedback on our concept idea from a clinical point of view, to obtain her opinion on the relevance of our cell therapy as well as its potential to have an impact on healthcare.

Contribution

Joyce Curvers was charmed by our improved project idea. She thought that it was very innovative and better than the previous design. In contrast to current therapies, our treatment would intervene the disease more early on as symptoms are controlled from inside the body. However, she still had some concerns about the choice of disease that we wanted to target. Although MDA5-positive dermatomyositis presents a well-defined autoantibody, the prevalence of MDA5-positive dermatomyositis is extremely low. More importantly, the anti-MDA5 antibodies are not pathogenic. This way, these antibodies are always present, also when the patient does not undergo relapses. Hereby, the cells would continuously excrete IL-10 resulting in continuous suppression of the immune system. This would lead to undesired side effects. Therefore, Joyce Curvers advised us to focus on the autoimmune disease ANCA-associated vasculitis (AAV) instead. AAV has a comparable severity to dermatomyositis, its prevalence is higher and it is characterized by pathogenic autoantibodies that fluctuate along with relapses of the disease. By engineering the cells such that they bind these autoantibodies, the cells would only excrete IL-10 when a patient undergoes a relapse (so when the disease is active). From a clinical point of view, this would improve the relevance of the treatment compared to current treatments as well as it would enhance the responsiveness for clinical use.

Implementation

We think that the main requirement of our cell therapy is that it responds to the fluctuations of an autoimmune disease. This way, the treatment will be preventive, tailored to the needs of the patient (personalized), and reduces side effects. From the discussion with Joyce Curvers, we learned that our proposed project idea, focused on dermatomyositis, did not meet that main requirement and that it does not fit the purpose of our treatment. Therefore, we choose to use the feedback obtained from Joyce Curvers to delve deeper into other autoimmune diseases again that better suit our requirements.

Outlook

To improve the clinical relevance of !MPACT, we should explore more appropriate autoimmune diseases such as AAV. To do this successfully, last time Joyce Curver already advised us to speak to more University Medical Centers (UMCs). Now we finally succeeded in planning a meeting with Erasmus Medical Center and Maastricht University Medical Center. After this, we envision that we should critically reflect on all the feedback gained from these stakeholders, to decide what autoimmune disease we want to focus on.

Purpose

In addition to validating our project with different hospitals and UMCs, we want to validate our project from another perspective. Therefore, we have set up a meeting with Martijn Meens, the Director of Chemical & Life Sciences at TMC, a high-tech consultancy company. In this meeting, we mainly focus on the concept of our therapy in general instead of the associated disease to gather more feedback on our concept as a whole.

Contribution

First, Martijn Meens emphasized that the presentations we give about our concept, in general, should be clear, simple, and understandable for everybody. Our presentation was already quite in-depth, which would not be suitable for every presentation and every audience. Instead, we should adjust presentations to the audience. Besides, Martijn mentioned that there are several connections and collaborations between pharmaceutical companies, UMCs, and hospitals. For example, they collaborate on research. UMCs and research institutes show evidence to pharmaceuticals on treatment effectiveness. The connections between UMCs, hospitals, and pharmaceuticals are very important. This is something we should be aware of. Finally, we talked about healthcare insurance. We learned that hospitals can only administer medication if the treatment is in the healthcare insurance. Doctors often discuss with healthcare insurance about what therapeutics should be reimbursed. Martijn advised us to gather insights into what therapeutics get insured and how these get into healthcare insurance.

Implementation

As we got feedback on the complexity of the presentation, we made three different presentations, each with another level of complexity. In this way, we can give stakeholders a presentation that fits their expertise better so that people can understand our project to a greater extent. Creating different presentations forced us to critically think about the main message we wanted to convey. Besides, it helped us to minimize the complexity of our project and to define our core concept in simple language. In addition, we included the implementation of our therapy in the presentations.

Outlook

To follow up on the advice received, we will investigate the decision process of therapeutics that will get in the health insurance. We will look into the associated stakeholders, and try to contact them to discuss who decides what therapeutics will be insured and what this trajectory looks like. Therefore, we aim to talk to pharmaceutical companies and the Zorginstituut Nederland (National Healthcare Institute of the Netherlands). Mapping this decision process will help us understand the future steps in getting our therapeutic to the market.

Purpose

The main requirements for the autoimmune disease we aim to treat with !MPACT includes that it needs to be a severe disease that is currently hard to treat, it must be characterized by pathogenic antibodies, and the autoantibody concentration in the blood should fluctuate along with the relapses of the disease. Dr. Joyce Curvers from Catharina Hospital Eindhoven had some doubts about our choice to focus on dermatomyositis since this disease did not meet the requirements. She advised us to focus on an autoimmune disease other than dermatomyositis. Consequently, Joyce Curvers recommended we take AAV into account. To make an appropriate choice for the disease we want to focus on, we need to gain more suggestions of suitable autoimmune diseases as well as feedback on the recommendation of AAV from other stakeholders. We, therefore, contacted Dr. Jan Damoiseaux. He is a laboratory specialist at Maastricht University Medical Center (Maastricht UMC) and specialized in medical immunology. The purpose of the meeting with Maastricht UMC is to discuss which diseases suit the requirements of our concept idea.

Contribution

Jan Damoiseaux was enthusiastic about the concept, but just like Joyce also doubted the choice of dermatomyositis. In addition, he emphasized that the autoantibody of MDA5 positive dermatomyositis patients is constantly present and thus does not fluctuate along with the relapses of the disease. He said that it is important to choose a disease in which the presence of a pathogenic antibody is proven. This is the case for AAV. Jan Damoiseaux mentioned that systemic lupus erythematosus (SLE) could also be a suitable disease. However, the pathogenic autoantibodies of SLE are antibodies against double-stranded DNA, which is not a protein and hence difficult to incorporate into our GEMS (Generalized extracellular molecule sensor platform) receptor. Important benefits that Jan Damoiseaux mentioned about focusing on AAV is that its symptoms are extremely severe and that its mortality rate is high. Moreover, the current treatments are burdensome and long-lasting. Therefore, our cell therapy, which intervenes more early on in the disease, would be a good and desirable improvement. One critical note of Jan Damoiseaux about using IL-10 is that we should take into account that not only the autoimmune reaction will be suppressed, but also other immune reactions.

Implementation

After the discussion with Maastricht UMC, we learned that dermatomyositis is not a suitable disease to focus on with our concept. Therefore, it is best for our project to change the disease we would like to treat with !MPACT. From the feedback obtained so far, recommendations have been given for AAV. However, we wanted to gain more input from additional stakeholders and literature to make a well-grounded choice.

Outlook

Our next step is to discuss possible autoimmune diseases for our concept with Erasmus Medical Center. In this discussion, we want to gain feedback on the recommendation of AAV, but also obtain recommendations for other diseases. The goal of this discussion with Erasmus Medical Center is to gain enough information, together with the information gained from other stakeholders and literature, to make a good and reasonable choice for the autoimmune disease that we wanted to focus on in our project.

Purpose

After our conversations with Maastricht UMC and Catharina Hospital, we learned that dermatomyositis might not be the best disease to treat with !MPACT. From both hospitals, we received the suggestion to focus on ANCA Associated Vasculitis (AAV). In this meeting with Erasmus Medical Center (Erasmus MC), we aim to validate the suggestion for AAV to learn if this disease will suit our project well.

Contribution

All participants of Erasmus MC were enthusiastic about our concept. They agreed with the concerns of MUMC and Catharina Hospital about dermatomyositis. Moreover, they agreed that AAV would be nice and suitable for our project. Besides, they also suggested another disease, namely Grave’s disease, which would also be suitable to focus on, as this disease also meets our main requirements previously explained. Even though currently most cases of Grave’s disease can be treated sufficiently, the cases in which Grave’s disease affects the eyes are not yet possible to treat in a non-surgical way. Therefore, our cell therapy !MPACT could be an effective new treatment to treat Grave’s disease patients in which the eyes are affected.

Implementation

After the meetings with MUMC, Catharina Hospital, and Erasmus MC, we combined all the information that we received. Based on this information, we decided that it would be better to change the disease we aim to treat with !MPACT since dermatomyositis is not an adequate proof of concept for a cell-based therapy that targets a pathogenic autoantibody and responds to relapses of the autoimmune disease.

Outlook

Our next step is to decide with our team which disease we will focus on in our project. To make a good choice, we should consider the suggestions and advice of the stakeholders we engaged. Furthermore, we should perform more in-depth research on the diseases that have been suggested to discover and discuss which disease best meets our requirements.

Purpose

The previous time we engaged with Organon, they advised us to consider the complete drug development process when designing a new therapy. To kick off our business plan we have had some interesting discussions with Novartis and ThermoFisher Scientific already. However, we still had some questions concerning the SWOT (Strengths, Weaknesses, Opportunities, and Threats)) and financial analysis we performed. Organon specializes in the production and marketing of medical products. Therefore, we decided to plan a meeting with Organon to get feedback on the viability of our business idea, the SWOT analysis, and the financial analysis we made for !MPACT.

Contribution

For the SWOT analysis, we received some useful input. Organon urged us to start thinking about intellectual property (IP) for our cell therapy design in the early phase of our project. This is often underestimated in start-ups and can cost a lot of money if an innovative idea is protected too late. Secondly, they said we had to think about our weaknesses and threats. They emphasized that there hides an opportunity in every weakness or threat. They, for example, explained that marketing a product can be difficult for a small company. Therefore, one should use the name of a large company to expand your network and add credibility to your product. For the financial analysis, they advised us to cut our entire project into smaller phases such as R&D, clinical trials, manufacturing, legislation, marketing, etc., and find out the estimated costs for each phase, to determine the total costs.

Implementation

We expanded our SWOT analysis based on the input from Organon and we learned that threats and weaknesses do not have to be bad but should be seen as opportunities. For every weakness and threat, we searched for new ways to circumvent them or use them to our advantage. We divided our project process into smaller phases for which we tried to predict the costs separately. This greatly helped us to develop a more reasonable financial plan. However, because of remaining uncertainties, we had to make numerous assumptions for the R&D phase, clinical trials, production, and legislation.

Outlook

To understand the complete drug development process and to achieve a more systemic approach to determine the costs of each phase, we think that it is valuable to speak to other stakeholders. In the next steps, we aim to identify and approach relevant stakeholders of each phase of the drug development pipeline, to engage them. Since the value proposition of !MPACT is still not fully clear, we also aim to contact Novartis again. Their expertise in the value proposition for cell therapies can help us to obtain a complete overview. Lastly, we must decide on a business strategy to address the question; how will we sell !MPACT?

Purpose

To gain a full understanding of the value proposition of !MPACT, we approached Novartis for a brainstorming session. The goal of this session was to determine the value of our product to the customers. This is crucial for determining the price of the product. In addition, our goal was to completely understand the supply chain and development process of cell therapies in general. Albert van Hell is experienced in developing Chimeric Antigen Receptor (CAR) T-cell therapies. CAR-T therapy is a treatment against various cancers, where the patient's immune cells (T-cells) are harvested from the body and genetically manipulated to attack tumor cells. Our team envisions using this therapy as a source of inspiration for the development of !MPACT. This interview will be used to implement safety measures that are necessary to successfully develop and administer our cell therapy.

Contribution

Regarding the value of !MPACT, the most important feedback we received was to focus on the calculated average yearly health improvement for the patient. If the price of !MPACT will be too high, society will not be able to pay for the treatment. On the other hand, if the price of the therapy is too low, no sufficient revenue will be received. Therefore, the price of a therapy should be determined based on the patient population size, the number of therapies needed per patient, and the improved quality of life. We learned that the price of !MPACT is based on multiple factors that include the value for the patient population.

Novartis believed that !MPACT is innovative because it is a personalized treatment that secreted interleukin 10 (IL-10) on demand. However, Albert advised us to carefully consider whether T-cells, which are used for CAR-T cell therapy, would work in our concept. Additionally, he suggested we should engage with experts that can teach us how to localize !MPACT at the site of inflammation. Therefore, he recommended we should interview an immunologist. In addition, Mark and Albert gave feedback regarding the logistic side of commercializing the product and advised us to investigate the scalability of !MPACT in more detail. This would ensure safe and reliable production. This factor is crucial for receiving market authorization.

Implementation

Based on the feedback regarding our cost structure, we adjusted the value proposition and price estimation of !MPACT by taking the value for the patient population into account. In addition, we calculated the relevant ANCA-associated vasculitis (AAV) population size. The human practices team discussed which experts are required to gain information on the localization of our cell therapy at the site of inflammation. Also, we discussed which experts could teach us how to scale out !MPACT

Outlook

To further investigate the design of our cell therapy and the corresponding safety measurements, we aim to interview an immunologist. Specifically, we aim to speak to Wilfred Germeraad, who is an associate professor in immunology at Maastricht University and the CSO of MedTech company CiMaas. In addition, we plan to engage with a clinical immunologist from Maastricht UMC who specializes in AAV. To understand the cell therapy production process, we plan to interview Johnson & Johnson, who recently have built new manufacturing facilities for CAR-T cell therapies. We aim to use these interviews to validate the information we got from Novartis to close the feedback cycle.

Purpose

During the pitching sessions of the TU/e contest (Communication), our goal was to pitch our project to different companies, and to learn whether our story, vision, and mission are clear.

Contribution

We presented our project in a one-minute pitch to Novartis, in which we explained why it is important to innovate autoimmune disease therapies and how our project could help accelerate this process. Based on this pitch, we received feedback from Mark van Hattum and Henrike Hartemink from Novartis. First, we learned how to improve the formulation of our unique selling point. This helped us to decide which values we should prioritize in our design. Beforehand, we were still doubtful whether to present our idea as a modular system for multiple autoimmune diseases or to focus on one specific disease. Together with Mark van Hattum we brainstormed about this decision. Besides that, we learned that at this stage it is difficult for pharmaceutical companies to invest in a project like ours. For investment by pharmaceutical companies, it is crucial to have developed a proof of concept and performed some form of a clinical trial.

Implementation

Improving our unique selling point helped us to understand our main mission and goal better. Therefore, we are now able to portray this mission better in future pitches and conversations with stakeholders. In addition, we shaped our mission based on the discussion with Novartis. Our mission will be to design a cell-based therapeutic for autoimmune diseases, starting with vasculitis.

Outlook

The improved one-minute pitch is an important feature of spreading our mission to society, different stakeholders, and companies. We aim to test the improvement we made at least once at future events and in future conversations.

Purpose

Recently, we have decided to change the disease of focus for our cell therapy to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Thereafter, we discussed our improved cell therapy design with Novartis. During this discussion, we were advised to contact an immunologist to discuss the effectiveness of interleukin 10 (IL-10) production to treat AAV related symptoms. Therefore, we contacted internist Matthias Busch of Maastricht UMC. Maastricht UMC is the largest medical center that specializes in AAV. Matthias Busch is a PhD candidate who performs research on AAV. The goal of this meeting is to obtain more information about the current treatments and to gain insights into the clinical need for a new therapy for AAV.

Contribution

Matthias confirmed the potential of our newly designed cell therapy as it might show benefits compared to the current treatments for AAV available in the clinic. He explained that current treatments consist of different immunosuppressive therapies such as prednisone, rituximab, and/or cyclophosphamide. With these therapies, remission of AAV can be effectively achieved, however, they are also associated with a lot of side-effects. Therefore, immunosuppressive therapies are administered for only a limited amount of time to maintain remission. As a result, AAV can relapse in patients over time, which decreases the health situation of the patient and puts pressure on the healthcare. He explained that in some cases kidney failure could occur, leading to dialysis, low quality of life, and high healthcare costs, especially when kidney transplantation is not possible. He acknowledged that our therapy could have significant advantages as you only have to administer it once and because it responds to relapses immediately. This may prevent multiple hospitalizations for the patient. In addition, it could lead to fewer side effects, since it is more specific. Matthias explained that the workload and health care costs for hospitals to treat a relapse is high. Particularly at the start of a flare-up, (the first two months) intense guidance and monitoring of the patient is necessary. Hence, he saw crucial advantages from the clinical perspective as well.

On the contrary, he also had some critical notes about our designed cell therapy. He wasn’t sure if excretion of IL-10 would be potent enough to decrease inflammation associated with AAV, since this has not been proven in research for AAV. He advised us to look at papers that investigated the IL-10 concentration throughout AAV relapses. Moreover, he emphasized that different types of ANCAs are known (i.e., MPO-ANCA and PR3-ANCA) and antibody rises are not always directly related to disease flares. He advised us that we should specify for which patients the therapy could be a solution. Lastly, he encouraged us to look at how we could target autoantibody specific B cells (instead of producing IL-10) in the future since this better intervenes at the cause of the disease.

Implementation

We learned about the current treatments for AAV and the advantages of our designed cell therapy. Moreover, we gained more insights into the need for an improved therapy to treat AAV from a clinical point of view. We used the information gained to formulate clear selling points (advantages) of our designed cell therapy, which we implemented in our Communication. Also, we applied these to our pitches about our project and its business opportunity. The critical notes we received encouraged us to look into the literature to identify the role of IL-10 in AAV and the differences in autoantibodies between AAV patients.

Outlook

Our next step is to perform more literature studies on the role of IL-10 in AAV, the differences in expressed ANCAs between AAV patients, and how autoantibody-specific B cells could potentially be targeted in the outlook of our project. In addition, we plan to interview AAV patients that we want to contact via the Vasculitis Foundation. From these interviews, we want to learn about the pains and needs from a patient perspective. Furthermore, we aim to investigate the safety issues concerning !MPACT further. This, we want to achieve by engaging the RIVM.

Purpose

During the entire iGEM project, we meet several stakeholders to gather new information that we integrate into our project. This information also includes personal information from the stakeholders, which we must handle carefully and responsibly. To learn how we should handle gathered data responsibly and safely we have a meeting with the Ethical Review Board of the Eindhoven University of Technology.

Contribution

From the meeting with the Ethical Review Board, we learned that we need official permission from our university to interview stakeholders during the project. In addition, we learned that it is required to draft an informed consent, that must be signed by stakeholders that we interviewed. With this, we get permission to process the information that we gathered from them. Besides that, we are also planning to interview patients that suffer from ANCA-associated vasculitis (AAV). Since information obtained from patients is much more sensitive and confidential, we must handle this even more safely and responsibly. Therefore, the Ethical Review Board told us that we should make a separate informed consent for patients next to the informed consent for the experts. They also urged that we must mention in the consent form that we are participating in a competition and thus, that we are not yet planning on actually developing our therapy. The patients must not get false hopes. Furthermore, when collecting and processing the personal data of stakeholders, we must act according to the General Data Protection Regulation (GDPR), which is a European regulation that standardizes the rules for processing personal data across the European Union. To comply with this, the Ethical Review Board referred us to the data steward from our university. From this data steward, we can learn how we can process and store personal data safely and responsibly.

Implementation

The main lesson that we learned from the Ethical Review Board at the Eindhoven University of Technology is that we must act responsibly with the information that we will obtain from our stakeholders. Therefore, we have made two informed consents, one for patients and one for experts, that must be signed by the stakeholders to obtain permission to use their information. To validate if our informed consents include all obligatory information, we have sent them to the Ethical Review Board so they can review them and give official institutional permission for our research.

Outlook

To learn how we can process and store personal data safely and responsibly, our next step is to make an appointment with the data steward of our university. Next to this, we will send out the informed consents to all stakeholders that we already have spoken to and to new stakeholders as soon as the informed consent forms are reviewed and approved.

Purpose

Being part of the iGEM community, we believe safety issues outside the lab are of critical importance to consider in our project. To reflect on safety as broadly as possible, the first step was to discuss safety with the Rijksinstituut voor Volksgezondheid en Milieu (RIVM). The RIVM is the National Institute for Public Health and Environment of the Netherlands and is committed to establishing a healthy population and environment in the Netherlands. Dr. Cecile van der Vlugt-Bergmans has expertise in risk assessment of GMOs and advises on their safety management. Wessel Teunisse is Policy Advisor Safety of Nanomaterials. The goal of this first discussion with RIVM is to identify the possible risks and safety issues associated with our project. Moreover, the RIVM could help us to identify the relevant stakeholders we can approach to understand the risks and find out which measures should be taken to minimize and manage these risks.

Contribution

During the meeting, we learned what the consequences could be of !MPACT in terms of safety. For example, !MPACT possibly results in the generation of memory cells after injection. As a consequence of this, a patient will have genetically modified cells inside his or her body for the rest of his or her life. RIVM suggested that we should think about the consequences and possible risks for the patient in the long term. Next to the consequences for the patient the RIVM also emphasized possible risks for hospitals or during the transport of the GMOs. We therefore should also consider the consequences and risks to the environment. Lastly, the RIVM suggested some stakeholders we could contact to discuss the above-mentioned risks of !MPACT. They advised speaking to the Centraal Bureau of Geneesmiddelen (CBG) or EMA (European Medicines Agency). The CBG is an independent authority in the Netherlands for the regulation of the quality, effect, and safety of a medicine. They also suggested some parties we could approach who might have a more skeptical attitude towards synthetic biology, for example, Greenpeace.

Implementation

After the meeting with RIVM, we reflected on all safety issues correlated to our project and we tried to map all the different risks. Based on these risks we tried to identify, together with the input of the RIVM, the stakeholders that would be relevant to the approach. For example, we tried to contact the CBG or the EMA to discuss the safety measures necessary for market authorization. Also, we contacted Johnson & Johnson which is building a new facility for cell-therapy production. Together with Johnson & Johnson, we could discuss safety issues during production and transport. In addition, we tried to contact a hospital that administers cell therapies to discuss the risks of the administration of cell therapies in the hospital. Lastly, the RIVM provided us with safety cases as homework. These cases are focused on safety for the environment. The cases stimulated creative thinking and enriched our knowledge on different safety issues that could be correlated to new GMOs.

Outlook

The next step is to discuss all identified safety issues with the relevant stakeholders. We aim to incorporate safety in the broadest sense possible. A second meeting with the RIVM will be planned to discuss the conversations we have had regarding safety considerations and how we applied the knowledge we gained to our project. Moreover, we will discuss the safety issues of our cell therapy regarding the environment with the RIVM in the next meeting as well. Lastly, in the future, we aim to discuss which people could be negatively affected by our designed therapy or which people could misuse our cell therapy !MPACT

Purpose

At this moment, our project design is determined and the experiments to test and verify our proof of concept are prepared. To conduct the experiments safely and responsibly, we wanted to discuss the planned experiments, and the corresponding lab safety issues and risks with the BioSafety Officer (BSO) of our institution. Moreover, we want to discuss the Project Safety Form with her to make sure we communicate our biosafety precautions to the iGEM competition in a concise way.

Contribution

Together with Liesbeth Varion (BSO) of our institution, we discussed all the experimental protocols and the complete Project Safety Form. Liesbeth taught us the main risks of the experiments and the precautions that we should take to minimize them. She explained for which experiments it is mandatory to work in the biosafety cabinet and what we must do when we spill contaminated material. In addition, she checked whether all parts and cells we will use are covered by the GMO license of our institution. Lastly, she provided feedback and additions on our Project Safety Form for the iGEM competition. She shared some links for the GMO and biotech-related laws and regulations in the Netherlands and she gave biosafety information about the interleukin 10 (IL-10) protein and antibodies we want to use in the lab.

Implementation

Based on the feedback on the safety aspects and risks of our experiments, we implemented necessary safety precautions into the experiment protocols. We added extra precautions to make sure we work in a sterile environment to protect ourselves, the experiment, and the environment. These precautions include how and when to use the biosafety cabinet, how to prevent the spread of aerosols, how to deal with spills, how to prevent contamination, etc. We improved the Project Safety Form by adding biosafety information on the antibodies, Il-10 protein, and cells we want to engineer. In addition, we added the risks that are inherent to our lab work and how we plan to minimize these risks in the Project Safety From. More information about lab safety measures can be found on our Safety page.

Outlook

Concerning lab safety, we will ask for feedback from Post-Docs and PhD’ers, who guide us in the lab, on how well we put the safety precautions into practice. If the experiments or our project partly changes, we will reach out to the BSO again to discuss the updates. As also explained in the meeting with the RIVM, we plan to look at safety from other perspectives such as the environment, production, administration, patient, clinical trials, and legislation.

Purpose

The stakeholders we have spoken to so far mainly helped us with the design of our cell therapy, the disease we should focus on with our cell therapy, and how to set up a business plan. Although we already gained useful information from these stakeholders, we also wanted to implement the feedback obtained by future users: the ANCA-associated Vasculitis (AAV) patients. Therefore, we contacted Peter Verhoeven, the chairman of the Vasculitis Foundation in the Netherlands, to learn more about AAV and how patients experience living with it. Therefore, the purpose of the meeting with Peter is to learn more about the activities of the Vasculitis Foundation, how AAV influences the life of patients, and how patients experience current diagnostic tools, care infrastructure, and treatments. Moreover, we want to get feedback on the design of our cell therapy from the perspective of the users to learn whether patients are willing to ‘use’ !MPACT.

Contribution

From our conversation with Peter Verhoeven, we learned that the Vasculitis Foundation mainly focuses on supporting AAV patients. AAV is a rare autoimmune disease. Therefore, most people are not familiar with this disease, including several doctors. Due to this problem, the diagnosis process can take three to four years, wherein misunderstanding arises among the patients. The Vasculitis Foundation stands up for these AAV patients by facilitating contact between patients, providing information about AAV to society, and meeting the needs of patients.

In addition, Peter explained to us that people who suffer from AAV are treated with a high dose of medicine over six months followed by a maintenance treatment of prednisone to calm down the immune system. However, these current treatments do not treat AAV patients completely. Besides, patients can undergo a relapse after two to three years and they face a lifetime of extreme weariness.

After receiving all this information about the Vasculitis Foundation and AAV patients, we explained our project to Peter. Peter thought that our treatment is appealing to patients. He told us that he believes that patients would be very happy to receive our treatment instead of the burdensome current treatments. Compared to the current treatments, our treatment would respond better to the disease, which decreases the side effects for the patient. Peter explained to us that patients would not be very hesitant about our treatment, since they trust new therapies if they are provided with reliable and clear information by experts.

Implementation

The conversation with Peter taught us that AAV is even more invasive for the patient than we anticipated. From this, we learned that it is important that the current treatments continuously improve to treat the patients in a better way and to improve their quality of life. To contribute to this, we think that it is important that our project is responsive to the needs of AAV patients. Therefore, we aim to learn more about the needs of patients so that we can implement this in our project. Moreover, based on information we received from Peter about AAV patients, we created a patient journey and infographic about AAV.

Outlook

To build further upon our knowledge about AAV patients, we are planning to interview several AAV patients, with whom we can get in contact through the Vasculitis Foundation. From these interviews, we will obtain a better understanding of how patients experience AAV and how they feel about our project. This would help us to increase the responsiveness of our project by improving its feasibility and desirability.

Purpose

From the meeting with the Ethical Review Board of Eindhoven University of Technology (TU/e), we learned that we must handle information obtained from stakeholders responsibly. To learn how to act responsibly, we have a meeting with Anne Aarts, the data steward at the TU/e. The goal is to learn how to receive, process, and store personal data safely and responsibly.

Contribution

From the meeting with the Ethical Review Board, we already learned that we should have two informed consents, one for patients and one for the experts we interview. Anne elaborated on the informed consent and mentioned that two aspects should be considered to act safely and responsibly. One is from an ethical point of view: It should be clear from the informed consent that stakeholders are part of a study, that they know what participation entails, and that it is voluntary. The second aspect relates to privacy laws: Informed consent should entail what data is used, how and by whom it is processed, and how long it will be stored. As a final remark about the informed consent, Anne mentioned that people should perform active handling to give their consent. Another thing we learned from this meeting is that our project is classified as a low-risk project, since not much sensitive data is involved. We can still minimize risks by anonymizing the data, storing it as short as possible, and by omitting redundant data. Nevertheless, we concluded that the tool we used to store our data did not meet the safety requirements. Anne advised us to use a server from the university or at least a tool supported by the university, as they are maintained by the IT department and automatically backup. Finally, to minimize the risks with sensitive data, as few people as possible should have access to the data.

Implementation

The input from Anne helped us to understand the safety regulations of the TU/e that we must follow. Besides, it made us even more aware of the importance of working safely and responsibly and how to act accordingly. By being transparent in our informed consent, we follow iGEM’s values. For example, the value of honesty as we make clear that the therapy !MPACT will not reach the market any time soon, so it is only for study purposes. Moreover, we learned how to handle sensitive data securely and we became aware of the importance of a suitable server to store our data. Lastly, we created a privacy impact assessment (PIA) for safe data collection, processing and storage. These safety measures serve as a foundation for future iGEM teams of TU Eindhoven.

Outlook

We will wait for approval of our informed consent forms, our PIA proposal and our research project proposal.

Purpose

Until now we have discussed our business plan with multiple stakeholders such as Novartis, Organon, and ThermoFisher Scientific. We found out while working on our business plan that is crucial to legally protect your new technology as early as possible. The Gate is an initiative that helps students and start-ups in their starting phase as a team or company. They offer, for example, advice on intellectual property. Besides, they request patent applications for employees of the Technical University of Eindhoven, if the subject is promising from both patentability and valorization perspectives. The first goal of our meeting with The Gate is to learn how to communicate about the technologies of others that we build upon with our project. Secondly, we want to discuss the possibilities for patenting our project. Our team was initially not planning to investigate the intellectual property and a patent for our project !MPACT. However, Bart Grevenhof of The Gate contacted us to discuss the possibility of legally protecting our project. Although there are only a few months left before the Grand Jamboree, it seems interesting to us to discuss the possibilities regarding patenting our project and the restrictions regarding referring to previous work and technologies.

Contribution

Anna Wetzels explained that the published US patent application that we found, relating to the GEMS (Generalized extracellular molecule sensor platform) system we use in our project, has not yet resulted in any patents anywhere in the world and that there was no corresponding European patent application. This meant that the publication did not present a legal barrier for our student project in Europe. Still, we learned from Anna that it is important to give everyone that contributes to the project the right credits in all the work and deliverables, for instance, presentations, the website, and on social media. This helped us to understand how we should handle other people's contributions to our project.

Regarding patenting opportunities, Anna explained to us that it is important that we do not disclose the information that we want to patent. We can file a patent application (the preparation of which can take as little as two weeks) and apply for a relatively low-cost Dutch patent. An international, much more expensive, application could then be filed within a year of the initial filing. Patenting a system or technology requires that it should be new, not obvious, and capable of industrial applicability. In theory, it would be possible to apply for a patent on our technology before the iGEM Grand Jamboree in Paris where we need to present the technology. However, we already disclosed large parts of the project while validating our project with stakeholders, and, as a result, we are not able to patent the current technology anymore. Bart and Anna advised us to discuss within the team whether there are adjustments to our project that we did not disclose yet and we want to patent.

Implementation

We checked if we gave the developer of the GEMS system the right credits throughout our project and in all our written content. Besides, we discussed patenting our technology in the weekly team meeting. We created more awareness about intellectual property within the team and discussed that disclosing information should have a clear purpose. Validating our project and presenting the project during the iGEM competition is an example of suitable purposes to disclose our technology, but for instance, revealing non-related information about our project to stakeholders should be limited. We aim to optimize !MPACT after the Grand Jamboree where we will extend on the current technology used to be able to patent our proof of concept. In addition, we discussed that, from that point in time we will use non-disclosure agreements or ask for people's confidentiality.

Outlook

Our team decided to keep the possibility of a patenting application in mind for after the Grand Jamboree.

Purpose

During previous meetings with Organon, TMC, RIVM and Novartis, we concluded that implementation of our cell therapy is crucial for its design. The purpose of this interview is to understand the laws and regulations concerning the authorization and marketing of ATMPs (Advanced Therapy Medicinal Products), in particular cell therapies, in the EU (and the USA). Moreover, the goal is to understand the authorization process for the cell therapy and the role of the European Medicines Agency (EMA).

Secondly, the purpose is to obtain insights into the risks of developing a new cell therapy and to identify the parties that can be negatively affected by bringing !MPACT on the market. Besides, the question is whether and how our product could be misused. We want to find out how we could minimize these risks and concerns. Koosje van Lessen Kloeke is Life Sciences and Healthcare Lawyer and is familiar with the rules and regulations regarding ATMPs.

Contribution

Koosje firstly explained some of the regulatory requirements for an organization to reach EMA authorization of a cell therapy. It starts with the right qualifications for performing the necessary research. If you want to become commercial, you need manufacturing authorizations and, if applicable, authorizations for exporting and importing medicines. To get marketing authorization from the European Commission, after an assessment by EMA, you need evidence (data) to support ATMPs' quality, safety, and efficacy based on which the regulatory authorities (EMA) can do a benefit-risk assessment. Therefore, you must conduct appropriate clinical studies for which you also need the necessary regulatory approvals. Koosje stressed that after obtaining a marketing authorization, the authorization holder will be required to continue collecting data and may be required to perform follow-up research on the safety and efficacy of your authorized medicine and such data must be shared with the EMA. She also emphasized that market access not only requires market authorization but also reimbursements. In the Netherlands, health insurance companies play an important role in this. The Ministry, and in some cases also the insurance companies, negotiate about the price and could require additional data. Important to realize is that all countries have different laws and regulations, and different reimbursement authorities/payors are involved, which demands different strategies for market access.

In addition, Koosje explained in the interview that safety is an essential topic for pharmaceutical companies and anyone working with ATMPs. Safety is crucial in every law and regulation in some way. She explained that compliance issues should be reviewed when you bring a cell therapy to the market from a law point of view. She made clear that you should pay attention to your partners such as hospital labs or advisors who should be qualified and should also have the authorizations required. In addition, you must report all data, even data that could be negative for your selling your cell therapy. Moreover, a bottleneck can be environmental regulations such as GMO licenses.

Lastly, Koosje taught us which parties could be involved in discussions about ATMPs and that it is important to be aware of any (negative) perceptions surrounding ATMPs, for example, related to pricing and reimbursement. Moreover, she explained the importance of communication and public affairs to address certain perceptions. She forwarded us to Peter Bertens of Vereniging Innovatieve Geneesmiddelen (VIG) to elaborate on this topic.

Implementation

The interview with Koosje gave our team insight into the complicated and tightly regulated AMTP regulation. We implemented this in all phases of the drug development process for the proposed implementation of our project. The safety considerations we learned from this interview are also integrated in this wiki page.

Outlook

Koosje brought it to our attention that it would be interesting for our team to speak to someone from the ‘Vereniging Innovatieve Geneesmiddelen (VIG). Therefore, she proposed to bring us in contact with the relevant representative of this association, Peter Bertens. The VIG represents innovative medicine companies in the Netherlands. We aim to plan a meeting with Peter Bertens to discuss the impact of new medicine and therapies on society and how to best interact and communicate about our project.

Purpose

Novartis previously advised us to validate our project together with an immunologist who specializes in cell therapies. Therefore, we planned a meeting with Dr. Wilfred Germeraad from CiMaas. CiMaas is a med-tech startup that aims to achieve a better cure for cancer by developing cell therapies that engage the immune system. Wilfred is the CSO of CiMaas and is trained as an immunologist. Therefore, he has expertise in developing cell therapies that make use of the immune system and has experience in running a start-up in the medical technology field. The goal for the meeting with Wilfred is therefore two-fold. First, we would like to get insights into the outlook design of our cell therapy, and second, we would like to gain information about which steps a med-tech start-up has to take to grow successfully.

Contribution

After we showed Wilfred our project idea, he immediately shared some critical notes. He explains that there are cheaper methods to get IL-10 locally at the site of inflammation instead of using an expensive and risky cell therapy. A cell therapy would only be viable if memory cells were produced such that the therapy can respond for a longer timespan (years) to the relapses of AAV. To get memory cells, the injected cells must get activated. Wilfred doubts if T cells could get activated through antibodies. Therefore, he suggested considering other immune cells. B-cells, for instance, can get activated and form memory B cells after binding antigens. Secondly, Wilfred shared the key steps you need to take as a med-tech start-up to grow. He explained the cost structure a med-tech start-up is facing. He for example advised us to continue the drug development process until clinical phase 2A. This is often enough evidence for the proof of concept to successfully license the IP to a large pharmaceutical company.

Implementation

Based on the input from Wilfred about the cell type of our prospective cell therapy, we decided to do literature studies on B-cell therapies, B-cell activation, and the production of memory B cells. In addition, we implemented the information we gained on revenue streams and cost structure for a start-up in our business plan (Entrepreneurship).

Outlook

Based on a combination of literature study and the discussion with Dr. Germeraad, we will decide which immune cells we should choose for cell therapy !MPACT. To make this decision, we will make an inventory of which requirements that we have set for our project are met by B- or T-cells. After this, the next step is to complete our prospective cell therapy idea. We must think about how we can get the cell therapy locally. Thereafter, we would like to validate our improved prospective cell therapy idea with experts from the Erasmus MC. Besides, we must implement all obtained information about the business around our cell therapy into the business plan.

Purpose

Until now, we have gathered information on how to design a cell therapy, how to set up a business plan, and which regulations must be followed. From the meetings with these stakeholders, we learned a lot about the development process of cell therapies. Besides all the insights gathered so far, we think that it is also important to take the user’s perspective into account in the process of developing our project. Therefore, we contacted the Vasculitis Foundation and we also made contact with Dr. van der Poel, who is an internist and hematologist at the Maastricht University Medical Center (MUMC). She is responsible for all activities around Chimeric Antigen Receptor (CAR) T-cell therapies that are performed at MUMC. CAR-T therapy is a treatment against various cancers, where the patient's immune cells (T-cells) are harvested from the body and genetically manipulated to attack tumor cells. The purpose of this meeting is to learn more about the CAR T-cell administration process and the corresponding risks and safety issues. In addition, we want to learn what side effects may arise and how the patients experience the CAR T-cell therapy. Furthermore, we want to use the feedback that we receive to improve the design of our cell therapy.

Contribution

Dr. van der Poel explained that before CAR T-cell administration a selection process must be carried out, to which strict criteria apply. In this process, patients are screened for their tumor, heart, and lung function. This strict selection procedure is important, due to the invasiveness of the therapy. Therefore, patients are only treated with this therapy if a patient has bad prospects and there is no other therapy available left that is less invasive.

The most common side effect after treatment is cytokine release syndrome, which affects 90% of the patients. This syndrome can occur in different gradations. Depending on the severity, patients are given medication to suppress the syndrome. Besides this, patients can experience neurological side effects. Dr. van der Poel taught us that the main risk of cell therapy arises when a patient must be admitted to the ICU (Intensive Care Unit). However, most patients that end up here almost always recover.

Dr. van der Poel noted that the patient’s experience with the CAR T-cell therapy varies, depending on the experienced side effects. Patients that suffered from neurological side effects experience the therapy as intense, whereas patients that did not suffer from this find the therapy to be mild.

After explaining our project to Dr. van der Poel, she told us that our project is very innovative and ambitious. She believed that the main challenge of our project is the production time of the cell therapy. For CAR T-cells, this time is 3.5 weeks. For a critical cancer patient, this is often too long. Therefore, it is important that the cells can be engineered on a shorter time scale. Another challenge that she mentioned was that we must consider how we could intervene if too much IL-10 is produced. In addition, Dr. van der Poel had some doubts about the persistence of our injected cells, as the persistence of cell therapies is usually no longer than a few years. She thinks that the persistence of the cells is an important part of our project. Furthermore, Dr. van der Poel believes that the willingness of patients to undergo cell therapy depends on the severity and mortality of the disease. If this is high, patients are more willing to accept the side effects that may arise from the treatment.

Implementation

From this interview, we obtained a clear overview of the possible side effects that may arise from cell therapies. This is important when comparing our cell therapy with alternative treatments that are currently on the market for treating AAV.

Dr. Marjolein van der Poel gave us some useful feedback on the challenges that we need to consider in the design of our project. Based on this feedback we will perform literature studies on the persistence of cell therapies. In addition, we will perform more research on how to manage IL-10 expression, as well as how to intervene in IL-10 overexpression. The administration process of a cell therapy is integrated in the proposed implementation.

Outlook

We are planning on interviewing patients that are diagnosed with AAV to get a better understanding of their experience with the current treatments and their willingness to undergo our cell therapy.

Purpose

After the meeting with Lawyer Koosje van Lessen-Kloeke about the laws and regulations regarding market authorization and market access of ATMPs we wanted to learn more about the clinical studies for Advanced therapy medicinal products (ATMPs). Center for Human Drug Research (CHDR) is an institute specializing in early-stage clinical drug research. CHDR can help us to understand the complete clinical trial process for ATMPs, what the costs of a clinical trial process could be, and what happens when something unintended happens. Dr. Jeroen van Smeden is the educational director at CHDR.

Contribution

In the Netherlands, it is necessary to get permission from the Central Committee on Human Research (CCMO) before you can perform clinical trials. In the case of ATMPs, the minister of public health must give permission as well. To realize permission for clinical trials, much paperwork, like forms and protocols, must be delivered. We found out that the costs for clinical trials depend on the potential of therapies to reach the market. Jeroen mentioned that only a few therapies get through all clinical trial stages and can enter the market. On average, only 1 out of 10 therapies make it to the market after the clinical trials on humans started. This is thus a high risk when starting a clinical trial. In addition, because the costs of clinical trials for medicines that eventually will not enter the market should be covered as well, clinical trials are expensive.

Besides, we discussed the process of clinical trials. It is important to check the functioning of medicine and its efficiency in those studies. Next to the preclinical trials, animal studies and tests on healthy people will be performed. To ensure safety, very low doses will be administered, and several vital functions are measured during the study, such as temperature, kidney function, liver function, and an ECG will be made. People are not only screened during the trials but also before and after the trials. Screening is especially important for medicines for autoimmune diseases because the immune response in animals differs from the one in humans. As a result, unexpected consequences can occur during clinical trials in humans, like a cytokine storm.

Next, we learned what is done when something goes unintended in the clinical trial process, like the observation of unexpected side effects, or a minor incident. This heavily depends on the cause of the incident. Therefore, in case something goes wrong, first the cause of the event will be determined. Depending on the type of event and side effects, the study will be stopped or not. For example, if a person gets ill during the process as a result of allergies, the study can continue, however, this person is expelled from the study. Jeroen van Smeden also explained the importance of preventing accidents from happening, and how CHDR takes preventative measures.

Finally, Jeroen mentioned that whether medicine or therapy will be insured depends on its quality-adjusted life year (QALY). This measure will be used to make an economical consideration of whether a medicine should be insured. Besides, one will look at the ICER which compares the costs and the benefits.

Implementation

This interview gave us insights into several aspects of clinical trials. From the discussion with Jeroen van Smeden, we learned that getting permission for clinical trials is a strict process, and the application for clinical trials for ATMPs has even more requirements. In addition, we learned that accomplishing all clinical trials for medicines for auto-immune diseases can be quite hard. It made us even more aware of the importance of a safe design of the therapy, and it triggered us to think about the kill switch concept or self-inhibition of the system. We integrated all this in the proposed implementation. Next, we got insights into the costs of clinical trials and the costs of medicines which we consider for the entrepreneurship part of our project.

Outlook

Our next step is to interview the Johnson&Johnson to discuss the production process of cell therapies. Besides, we will implement the obtained information about the costs of clinical studies in the business plan.

Purpose

To understand the complete drug development process, we had meetings with CHDR to gain information about clinical trials, with lawyer Koosje van Lessen Kloeke to gain information about legislation, and with dr. van der Poel to learn more about the application by the end-user. One important step we have not yet addressed is the manufacturing of cell therapies. Organon already previously advised us to investigate the production of cell therapies and encouraged us to engage a manufacturer. Johnson & Johnson is building a new production facility for CAR-T cell therapies. Therefore, they are experts concerning requirements for new production facilities and the corresponding safety issues. Hence, the purpose of this interview is to understand the cell therapy production process and the corresponding safety issues and risks.

Contribution

At first, they explained that the efficiency of the manufacturing process determines the vein-to-vein time (the time from taking the patient’s cell to the injection of the cell therapy) of a cell therapy. The goal should be to constantly reduce the vein-to-vein time by optimizing the production process. Secondly, it is important to have a good balance between GMP (good manufacturing process) and safety measures that often ask for contradictory actions. Thirdly, they explained the safety conditions, which are necessary for the different steps of the production process, are executed in different biosafety level rooms. They stressed that the safety of production is not only restricted to the manufacturing facility. You should also take into consideration the transport (packaging, conditions, way of transport) and the protocols by hospitals.

Lastly, they explained that the manufacturing process also translates to the cell therapy design. They advised designing it in such a way that a minimal amount of lentivirus is necessary to insert the relevant genes when we would scale out the cell production. Lentiviruses bring in more risks, are more expensive, and require more safety measures to store them responsibly.

Implementation

We implemented all the safety measures for the production process in the proposed implementation of !MPACT. Additionally, we proposed alternative safer methods to modify the genome of the cells instead of using lentiviruses for example using mRNA.

Outlook

We got scientific papers from Johnson & Johnson about the production process and manufacturing facilities of cell therapies that we want to study for the proposed implementation of !MPACT. In the next steps, we also want to look at other phases of the drug development process such as market approval by the EMA and reimbursement of new medicine. 

Purpose

Lawyer Koosje van Lessen-Kloeke advised us to speak to Peter Bertens. To design our cell therapy in a good and responsible manner, we wanted to understand the impact and potential risks of the cell therapy on all groups of society. The purpose of this interview with Peter Bertens from the Vereniging Innovatieve Geneesmiddelen (VIG) is therefore to discuss the impact of our cell therapy on society and to find out which parties can get positively or negatively impacted by our project. Besides, we want to discuss the possible risks of bringing this innovative cell therapy into society and how to minimize those. Finally, we wanted to discuss how we should successfully inform, communicate, and work with relevant authorities or with stakeholders about potential risks related to our project.

Contribution

Peter emphasized the importance of safety during the design and development of a new cell therapy. To ensure the safety of the therapy, animal trials are often required. Since a part of society is against animal testing, our therapy could lead to new problems, for example, fewer investors for our therapy, since many investors do not support animal testing. To anticipate and minimize the impact of these concerns, Peter stressed the urgency of transparency, so that people understand how we do certain things and why. This could prevent misconceptions, he explained. Moreover, to prevent safety problems, it is crucial to contact the EMA (European Medicines Agency) as early as possible.

In addition, Peter mentioned that being in contact with patients, hospitals/doctors, scientists, and healthcare insurance is also important because these communities may be most interested or affected by our project. If our cell therapy would not be reimbursed by health insurance, it will most likely not reach the patient. Therefore, it is important that a therapy becomes part of the insured package and is reimbursed.

As said before, it is important to be transparent in the communication about the cell therapy to both stakeholders and the general public, also with the possible risks. Besides, it is not allowed to claim things about the therapy, like the number of people that will get better by the treatment. To successfully inform stakeholders, one should think of the audience, their knowledge of the topic, and their interests. Most people do not want to know all details about the mechanism of the therapy, since they also would not understand it.

Implementation

Peter gave us many insights about the way we should communicate about our therapy, which made us more aware of the importance of transparency, the importance of simplicity, and adjusting information to the specific stakeholders. We integrated this in the proposed implementation of our project.

Next, since Peter made us realize that the safety of the therapy is essential, we have dived deeper into this topic and reached out to related stakeholders such as the EMA , Zorginstituut Nederland (National Healthcare Institute of the Netherlands), and parties to speak about the dual-use of !MPACT.

Outlook

The next steps will be to meet with stakeholders who are experts on the dual-use of synthetic biology and the EMA to discuss market authorization. In addition, we will discuss the reimbursement (health insurance) for a new therapy with Zorginstituut Nederland.

Purpose

As explained in the previous meeting with Peter Bertens, we would like to know more about the potential dual use of our project. The purpose of interviewing dr. Mauritz Kelchtermans is to investigate the possible misuse of synthetic biology. Dr. Mauritz Kelchtermans has a PhD in chemistry, he is currently finishing his PhD Philosophy at KU Leuven, and he is a public speaker about the dangers of synthetic biology. With this interview, we aim to learn the possibilities of dual use of synthetic biology as well as which groups are negatively impacted because of synthetic biology. This interview is also part of our partnership with the iGEM team BOKU Vienna, in which we take the broadest view of synthetic biology and its associated ethical considerations into account.

Contribution

Dr. Mauritz Kelchtermans explained that the strict regulations for GMOs in Europe are among other things caused by the lobbying of non-profit organizations towards European parliamentarians. According to dr. Kelchtermans, the goal of these organizations, such as Greenpeace, is to prohibit GMOs. Because of this lobbying, the positive impacts of synthetic biology are not communicated to society sufficiently. According to dr. Kelchtermans, the current regulations should be more flexible nowadays. Nevertheless, sufficient control over GMO regulations should be maintained. In America, for instance, GMO regulations are less strict than in Europe. As a result, scientists experience more opportunities to solve world problems, such as climate change. Furthermore, in response to our question about whether there are ethical questions that remain undressed, dr. Kelchtermans explained to us that the current discussions are sufficient and are reflected in the stringent regulations in Europe.

Implementation

Mauritz Kelchtermans taught us that the regulations in Europe are strict, compared to America. However, change is coming, and with our iGEM project, we can drive this change. From our interview with dr. Kelchtermans, we learned that this change should move hand in hand with the current innovations. This inspirational interview, together with the environmental impact, inspired us even more to share the concept of !MPACT with the world. In the proposed implementation we have integrated the insights gained on comminication and rules & regulations of GMOs.

Outlook

Since dr. Mauritz Kelchtermans taught us non-profit organizations might have a significant impact on both the regulations of GMOs and the way that society sees synthetic biology, we aim to interview Greenpeace. With this interview, we can obtain a counterview on the use of synthetic biology to solve real-world problems. Moreover, we would like to speak to an expert in bioweapons to delve deeper into the dual use of synthetic biology and our project.

Purpose

In our interview with dr. Wilfred Germeraad from CiMaas, we learned that our cell therapy would only be viable if memory cells of the injected engineered cells were produced. In this way, the immune system would be controlled for a larger period. To obtain memory cells, activation of our engineered cells is required. To accomplish this, CiMaas suggested that B-cells would probably fit this design better than T-cells, as immune cells that naturally interact with antibodies are easiest to activate. To obtain more insights on which immune cells are most suitable for the implementation of our cell therapy, we contacted prof. Reno Debets, a professor in T cell immunity and adoptive therapy of tumors and chair of the Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Center, Rotterdam, the Netherlands. He has more than 20 years of experience in preclinical and clinical T cell-based research.

Contribution

Prof. Reno Debets was enthusiastic about our cell therapy. However, in comparison to CiMaas, Reno Debets recommended we use T-cells instead of B-cells. Firstly, T-cells are by definition very mobile cells. To prevent the presence of IL-10 throughout the whole body, in our project design it is desired that the cells excrete IL-10 locally. If the cells are mobile, they can move more easily to the location of inflammation where they would bind antibodies and get activated. This would result in a more local excretion of IL-10. Secondly, Reno Debets mentioned that it would be convenient if the cells that will be used in the therapy are natural producers of IL-10. According to Reno Debets, these arguments apply to T-cells rather than B-cells. Reno Debets agrees with CiMaas that it is important that memory cells will be produced. However, he thinks that this is rather a secondary requirement. It is more important to develop a cell that works and that locally excretes IL-10 to suppress the immune system. Moreover, even though it is not the easiest manner, Reno Debets thinks that the production of memory cells can also be achieved when using T-cells.

Implementation

From the meetings with CiMaas and prof. Reno Debets from Erasmus MC we obtained a clear overview of the pros and cons of implementing either T- or B-cells in our project design. We learned that both immune cells could suit our design but in different ways. Based on the insights gained we decided that we should determine which values and requirements must be prioritized in our cell therapy design and which compromises must be made. We integrated the overview of the different immune cells in our proposed implementation page.

Outlook

The next step is to make a well-considered, final decision upon which immune cells will be implemented in our cell therapy. To achieve this, we should decide which values and requirements we prioritize in our cell therapy. Therefore, we are planning to perform more literature studies on the arguments that have been given during the meetings with CiMaas and Erasmus MC.

Purpose

To get a better understanding and awareness of possible misuse or dual use of synthetic biology, we arranged a meeting with Dr. Koos van der Bruggen. He has tons of experience as an advisor on biosecurity. He worked for the Rathenau institute, which is an organization that performs research on the impact of science, innovation, and technology on society. Besides, he worked for the National Academies of Sciences to prepare and organize biosecurity activities in Indonesia. In addition, he was an adviser on biosecurity for the Royal Netherlands Academy of Arts and Sciences.

Moreover, Koos has written multiple papers on the use of life sciences as a bioweapon and has helped compose the code of conduct for biosecurity for the Netherlands. We hope to get insights into which measurements we can take to minimize the chance of synthetic biology, or our project getting misused. As a researcher himself, Koos van der Bruggen is pro-synthetic biology, but he believes research with dual use potential should be conducted via strict guidelines and the researcher should be aware of the dangers and its consequences.

Contribution

Koos explained the definition, history, and consequences of bioweapons. In addition, he explained possible threats and risks of synthetic biology in the future. We asked him how we could prevent the threats from becoming reality. He stressed that complete prevention is not possible but there are certain measures you can take to minimize the risks. For example, establishing a code of conduct, limiting access to the lab, screening new lab members, and keeping the trajectory of stocks and materials could minimize the risks. This will keep people with the wrong intention away from the biological agents. He said that biosecurity is as important as biosafety since the chance of accidents is even larger than deliberate misuse of biological agents. As a take-home message, he taught us that awareness among life scientists of possible misuse of their research is still limited and should be improved. However, awareness should not become so predominant that distrust is the default attitude in a laboratory. He believed that if we keep these measures in mind and work together, synthetic biology can be used to solve many problems in the future, although not all world problems could be solved with synthetic biology as with every new technology. We, thus, must remain realistic.

Implementation

Firstly, the meeting with Koos made us much more aware of the risks of misuse and dual use of synthetic biology and our project. Secondly, we now understand the risks and the consequences of bioweapons much better. At last, we got encouraged to read the Dutch Code of Conduct for Biosecurity. This made us aware of the measures needed to minimize the dual use of our technology. We concluded that most of these guidelines to prevent dual-use are already in place at our institution. We integrated these guidelines in the proposed implementation.

Outlook

Looking at the use of synthetic biology from a different perspective, we aim to speak to stakeholders such as Greenpeace who are skeptical about the use of synthetic biology in the environment.

Purpose

During several stakeholder interviews with vasculitis experts, we learned much about the need and desirability of our cell therapy to treat ANCA-associated vasculitis (AAV). In addition to this, we are aiming to learn how AAV patients experience the disease itself, its diagnostic process, care infrastructure, and its treatment. The best stakeholder who can teach us the experiences of patients is the patient himself. Moreover, we want to learn the desirability of !MPACT from the patients themselves. Therefore, we will interview five patients that are diagnosed with different types of AAV. These patients are associated with the Vasculitis Foundation and all vary in sex, age, and severity of the disease.

Contribution

The interviews with the AAV patients have taught us that the age and symptoms of patients can vary, ranging from fatigue, fever, and pain in joints, to paralyzed legs, kidney failure, and pneumonia. However, one thing that all patients have in common is the severity of the disease. Not only because of the symptoms but also because of the diagnostic process. This is mainly because most doctors are not familiar with AAV. Therefore, the diagnostic process is burdensome and takes an excessively large amount of time. During this process, the patients often felt confused and misunderstood.

Furthermore, the patients that we interviewed experienced the treatment as extremely burdensome. The therapies take several years in which the patient is exceptionally tired. Also, after treatment, many patients still suffer from the medical consequences of the treatment and disease. Moreover, several patients have experienced a relapse of the disease.

After explaining our project, the patients were enthusiastic about our cell therapy. They mentioned that there is a great need for a more personalized, specific treatment that leads to fewer side effects. Therefore, the patients were excessively supportive about !MPACT, which measures the severity of the disease and adjusts the secretion of the therapeutic accordingly.

To conclude, the interviews taught us that AAV has a serious impact on a patient’s life. To improve the diagnostic process, care infrastructure, and treatments of AAV, it is crucial to create more awareness about Vasculitis. Not only among patients and their families but also doctors. Hence, the work that is performed by the Vasculitis Foundation is incredibly important.

Implementation

The information obtained from the patient interviews was extremely valuable for our project. The stories from the patients motivated us even more to improve healthcare with our cell therapy for patients with this rare autoimmune disease. Therefore, we implemented the gained information in our project by mapping the experiences of patients living with ANCA-associated vasculitis in a patient journey map. This map was implemented in our business plan that has been elaborated for entrepreneurship. Besides this, we created a word cloud, containing all key elements that best describe the autoimmune disease AAV according to the patients (see below). Furthermore, we implemented the information about the experience of the patients in the promotional video of our project. As a consequence of patient interviews, we prioritized the regulation of interleukin 10 (IL-10) production in our project design to minimize side effects for the patients. We tried to address this challenge with our model and by designing an inhibition system (proposed implementation).

Outlook

The patient interviews helped us to obtain the overall desirability and feasibility of our project. The next step is to learn more about the potential environmental risks of !MPACT. To achieve this, we are aiming to plan a meeting with Greenpeace. Furthermore, we are planning to interview a public health organization, which the goal is to obtain insights into the inequality in access to health services in the world. Since we expect that !MPACT will be an expensive therapy, we want to learn which communities will be left out if our project succeeds.

Purpose

During the first meeting with the RIVM (National Institute for Public Health and the Environment), we discussed all possible safety issues for our project. Based on this discussion, we approached different types of stakeholders to discuss safety from different perspectives. For instance, we have discussed the safe production of GMOs, safe administration of cell therapies, safety in the lab, and safety for the patient with stakeholders. To close the loop, we planned a second meeting with the RIVM to discuss the progress we made and to ensure we have looked at the complete ‘safety picture’. Moreover, the goal of the second meeting with the RIVM is to understand the risks of GMOs (specifically cell therapies) to the environment & public health. Furthermore, we wanted to know what the values and roles of RIVM are in this process. Dr. Cecile van der Vlugt-Bergmans and Dr. Barbara te Riet-Schulte are experts in risk assessment of GMOs for public health and the environment.

Contribution

First, Cecile and Barbara gave some general feedback on our project. They encouraged us to process the implementation of our cell therapy, into our presentation for the Grand Jamboree. Secondly, they urged us to think about a way to inhibit the system (e.g. a killswitch) to prevent risks for the patient as well as for the environment from getting out of control. Especially because the immune system is tightly regulated, a feedback loop to inhibit and control the interleukin 10 (IL-10) production system is essential.

Furthermore, they elaborated on the risks and laws & regulations for GMOs in the environment. They explained that if you use GMOs for therapy, you also use them outside the laboratory. This means they are introduced into the environment, and in the Netherlands, a license is required by the Ministry of Infrastructure and Water Management, which requires an environmental risk analysis. Chimeric antigen receptor (CAR)-T cell therapies are already available in the market and are already approved for use in the environment. As our cell therapy has a large resemblance to CAR-T cell therapy, we could look at the CAR-T cell environmental risk analysis. It is expected that our cells cannot survive outside the human body. Therefore, minimal risks are expected for the environment and biodiversity. In the future, we expect we need lentiviruses to implement genes into human cells. The risks of lentiviral vectors are already known, and we can assess whether our CAR-T cell therapy falls in the scope of the current "Good Practice Documents for human genetically modified cells" that are available. However, we need to delve into the risks regarding the transfer of engineered cells from mother to child. Typically, this is tested during clinical trials and is reviewed by the CCMO (The Central Committee on Research Involving Human Subjects) and the EMA (European Medicines Agency).

Lastly, Cecile and Barbara elaborated on the role of the RIVM. The RIVM implements the laws and regulations based on the scientific knowledge available. They advise the ministry, which takes the ultimate decision for licensing new GMOs.

Implementation

Based on the feedback we received, we decided to process the implementation of our cell therapy in our final presentation. Moreover, we performed a literature study on ways to inhibit IL-10 production, which we processed into the proposed implementation section. The knowledge we gained about obtaining a license to enter the environment with our cell therapy is also incorporated in this section.

Outlook

To further investigate the risks to the environment of GMOs and to find out how a proper risk assessment is carried out, we decided to plan a meeting with Greenpeace. 

Purpose

One of the last phases of the drug development process is market access. When a new medicine receives market authorization, the Zorginstituut (National Healthcare Institute of the Netherlands) assesses whether it should be reimbursed from the basic health insurance package. The Zorginstituut advises the Minister of Health, Welfare, and Sport about the reimbursement of medicines. The purpose of the interview with the Zorginstituut is to understand the reimbursement of ATMPs (e.g., a cell therapy). Moreover, we would like to know more about the role of the Zorginstituut in this process. Finally, we would like to figure out the requirements for our cell therapy !MPACT to get reimbursed. Noraly Stam from the Zorginstituut specializes in the reimbursement of orphan drugs and could, therefore, help us to achieve our goals.

Contribution

First, Noraly explained the Dutch healthcare system that is based on the health triangle. At the three corners of the triangle, you have respectively the health insurer, the health care provider, and the insured patient. In addition, she explained the four tasks of the Zorginstituut. One of these tasks is giving advice about which medicines should be included in the health insurance to ensure that the healthcare in the Netherlands remains of high quality and affordable. If a medicine has been approved, the manufacturer can apply to the Zorginstituut for admission to the health insurance. Once the Zorginstituut has received all the information and scientific studies of the new drugs, they review, among others, how serious the associated disease is, how well the current drugs work, and in what groups of patients the medicine work. Whether a medicinal product is eligible for reimbursement is largely determined by its therapeutic value in comparison with the standard treatment used in the Netherlands and by evidence of its effectiveness. In addition, they look at the costs of the new therapy compared to its yield for the patient. Sometimes during the assessment, it appears to be uncertain if the effect of the treatment will remain consistent over time or that it does not seem to work in all patients. In that case, the Zorginstituut advises who should receive the medicine. If a drug is not cost-effective price negotiations can be advised. A price at which the drug will be most likely cost-effective, will be recommended. During the assessment process, the Zorginstituut tries to involve patient organizations, doctors, and health insurers. In addition, they get advice from 2 independent committees: the Scientific Advisory Board and the Package Advisory Committee. At last, Noraly gave some advice specifically for our cell therapy. She listed some questions which we should consider when we develop our therapy. One of these questions relates to the so-called lock for expensive drugs (formerly referred to as the ‘waiting room’ or ‘sluice’ for expensive drugs). If a new medicine is very expensive it could be placed in the lock by the Minister of VWS and follows a different procedure to get included in the basic package of the health insurance.

Implementation

Noraly gave us three take-home messages that we considered for our business plan. Firstly, we should consider if our therapy will be placed in the lock. Secondly, we had to think about how many and which patients we aim to treat with our therapy since fewer patients could mean a higher price for the therapy. Lastly, we got triggered to closely compare the existing medicines to treat ANCA-associated Vasculitis with !MPACT to determine whether !MPACT is significantly more effective. To see how we implemented this in our business plan you can visit our Entrepreneurship page.

Outlook

Together with Noraly, we discussed the process of reimbursement of new drugs in the Dutch basic healthcare package. However, during the discussion, we also concluded that this process is not the same in every country, and not every country has the resources nor the money to incorporate expensive innovative drugs into health insurance. However, since we, as an iGEM team, value equality a lot, we would like to discuss the consequences of expensive therapies on the inequality in healthcare access with a public health organization.

Purpose

Previously we have had discussions about multiple stages of the drug development process including research and development, production, clinical trials and market access. We also would like to discuss the market authorization of cell therapies and the role of the European Medicines Agency (EMA). Since the EMA has a key role in the EU regarding the market authorization of new medicines, it is important for us to understand the requirements for our cell therapy to access the market in the future. Secondly, we would like to discuss the role of the EMA in the authorization of clinical trials. Bert Leufkens, who has worked in several roles with the EMA, has experience in regulatory science and pharmaceutical policy. Therefore, he is the perfect candidate for this discussion.

Contribution

First, Bert mentioned that on a national level the CCMO (Central Committee on Human Research) is the leading authority in regulating clinical trials, not the EMA. But there is extensive collaboration with the EMA in order to foster European alignment and policy. Besides, we learned that the EMA does not give the final license for medicines to enter the market. Instead, the EMA reviews medicines and gives an opinion on the benefit-risk to the European Commission in Brussels which will make the final decision on market entry. The process of market authorization of ATMPs (Advanced therapy medicinal products) is similar to the process of many innovative medicines. They all must pass a central procedure. Developers are encouraged to contact and liaise with the EMA for scientific advice early in the process to support and supervise them during the development. In the meantime, the dossiers needed for market authorization are drafted. When the dossiers are completed, a scientific evaluation of the reports is conducted. Two EMA Committees are important here, i.e. the CAT (Committee for Advanced Therapies) and the CHMP (Committee for Medicinal Products for Human Use) The research will show if there is enough evidence that the medicine is suitable to enter the market. For authorization of cell therapies, two aspects are of special importance, namely a well-understood product characterization and enough evidence for efficacy and safety, i.e. a positive benefit-risk. The strict regulations for medicines are not limited to the process before entering the market, committees will also check data on the therapy post-authorization. For the development of medicines containing GMOs, there are additional national GMO regulations. In past years, medicines containing GMOs had many safety hiccups, however, currently increasing numbers of GMOs enter the market. Nevertheless, there remains a bottleneck, namely the high costs. Consequently, certain high-cost products may not enter the market in all European countries, albeit with a European license. Our cell therapy, which is meant as a solution might, therefore, result in inequalities between countries. However, Bert mentioned that the differences between countries already exist. Lastly, we learned that the EMA does not look primarily at the benefits of the new therapy over competitors or the comparative efficiency. The benefit-risk of the product under review is what counts. Bert mentioned that we must think of a good biomarker or another indicator that we can use in clinical trials to show the efficacy of the medicinal product.

Implementation

From this meeting, we obtained better insights into the process of market authorization of medicines, including the regulations for ATMPs which are applicable to our therapy. We became aware of the importance of having a biomarker that functions as a measure of the efficacy of our therapy. The mortality rate is not a very suitable marker for our therapy, as the mortality rate is currently very high. Besides, thanks to the tip from Bert we became aware that our therapy might belong to the category of orphan medicines, which can help to get extra incentives (market exclusivity, fee waivers). We implemented this in our business plan which can be found on the Entrepreneurship page. The process of market authorization we elaborated on in the proposed implementation.

Outlook

We will investigate the regulations for orphan medicines and their benefits based on the advice of Bert Leufkens.

Purpose

In the previous meeting with the RIVM (National Institute for Public Health and the Environment), we discussed the risks of !MPACT for the environment. We decided to plan a meeting with Greenpeace to further investigate the risks of GMOs to the environment and to find out their opinion concerning GMO legislation. Greenpeace has a more hesitant perspective on the use of synthetic biology in the environment. Therefore, we believe it is very interesting to hear their arguments and reasoning behind their opinion on new GMOs and the rise of synthetic biology. We will meet dr. Kevin Stairs who is Chemicals and Pollution Coordinator of the Greenpeace European Unit. He contributed to the article (“Danger Ahead, why gene editing is not the answer to the EU’s environmental challenges”.

Contribution

Dr. Stairs acknowledges that synthetic biology is a fast-developing sector with much potential but also potential dangers. As with the current EU discussions/debates regarding New Genomic Techniques (NGT), Greenpeace supports the European Court of Justice (ECJ) 2018 decision on NGTs that they are indeed subject to the existing GMO legislation and thereby must require robust, adequate risk assessment, traceability, and labeling. The decision of the ECJ is based on the interpretation of the existing GMO legislation and on the EU requirement to apply the Precautionary Principle. Dr. Stairs and Greenpeace agree with that Court ruling. Dr. Stairs explains that synthetic biology is far broader than NGT, but the basic principles are the same: avoid potential danger/harm. Dr. Stairs believes that all new technological developments should be subject to the application of the Precautionary Principle (PP). According to Kevin Stairs the PP, correctly applied requires the following:

1) Preventive action; 2) prior to scientific proof regarding cause and effect (at which time it is too often too late); 3) a shift in the burden of proof onto the proponent of the activity to demonstrate/prove the activity is unlikely to cause harm; and 4) implemented via an alternative, substitution, e.g., of materials, chemicals, techniques, technology.

Greenpeace believes that even if a risk is very low, but its consequences are potentially significant, a very strict risk assessment is necessary by an independent, objective third party. In this respect, a strict liability regime should apply, both for deterrence and best practice reasons, and compensatory justice reasons.

Implementation

Although we as an iGEM team are less hesitant about the use of synthetic biology in the environment, we do have the same opinion regarding risk minimalization and appropriate legislation. Therefore, we decided to incorporate risk assessment, traceability, and labeling for our new technology !MPACT in the “proposed implementation”. Moreover, we elaborated on the Precaution Principle in-depth to ensure !MPACT is safe for the environment when it enters the market.

Outlook

We expect that !MPACT will be an expensive therapy, seen the comparable Chimeric Antigen Receptor (CAR)-T cell therapy. This will merely be determined by its personalized nature and the complex production facilities needed to efficiently produce it on a large scale. Therefore, we would like to discuss the consequences of expensive therapies on the inequality in healthcare access between different countries and people with a public health organization.

We interviewed a consultant at one of the largest public health organizations in the world. Due to privacy, we will not name the organization nor the interviewee.

Purpose

During the meeting with the Zorginstituut (National Healthcare Institute of the Netherlands), we discussed the reimbursement of !MPACT in the Netherlands. However, the reimbursement regulations differ between countries. Since we expect that !MPACT will be very expensive, the purpose of this interview with the large public health organization is to discuss the inequality in access to health services in the world. Moreover, we would like to know what the cause of this inequality is and what we can do with our cell therapy to minimize the inequality in access to healthcare. Lastly, we want to know what the values of the public health organization are and what its role of it is in the process of enabling equal health services for everyone.

Contribution

The public health organization supports countries in moving their health systems towards universal health coverage, through equitable access to quality health services that are integrated, safe, and people-centered across the care continuum. They make universal health plans and policy plans for developing countries. Universal health means that each patient has the right to medical care which is internationally recognized. For each disease, the public health organization crystallizes out all minimal required clinical steps to treat the disease. The public health organization guides countries by helping them with what and who they minimally need to treat certain diseases and they give advice on where to invest in. For each country, they define the care that is needed, how much care is needed, and which treatments suit best. Subsequently, the government of the country can make a policy plan based on the advice of the public health organization.

According to the consultant, the differences in access to healthcare between certain countries are large due to two things: First, some countries do not have the financial resources to offer certain treatments, and second, they often lack a well-educated health workforce. Therefore, it is expected that poor developing countries will not offer Advanced Therapy Medical Products (ATMPs) like !MPACT. The fact that ANCA-associated Vasculitis (AAV) is a rare disease contributed to this expectation, since developing countries first seek to treat diseases with a high prevalence. Treatments for more prevalent diseases are more profitable to offer and help a larger part of their population. The consultant explained that the public health organization cannot do much to reduce the inequality in access to new ATMPs such as !MPACT. The responsibility lies with the manufacturer: The manufacturer should be willing to offer the therapy in certain countries for a lower price or even for free to help a larger population.

As a take-home message, the consultant explained that innovation is necessary, possibly with high costs. Later, it might become available in all countries. The consultant took the example of a CT scan which was very expensive at the beginning and only available in Western countries. Now, the costs of a CT scan are reduced, and CT scans are available in almost all countries.

Implementation

We implemented the information we received from the consultant. First, we discussed within our team whether it is ethically responsible that we treat AAV patients in only Western countries. We concluded that although we aim to treat patients from all countries we will have to start with Western countries, since they have the financial resources and healthcare workforce. As the consultant mentioned, often innovation is needed before medicines can be accessible in all countries; it is possible that !MPACT will become available in other countries in a few years. If sufficient revenue in rich countries is made, we aim to equalize access to healthcare in all countries.

Outlook

For the next steps, we will try to make more stakeholders in the pharmaceutical industry aware of the ethical discussion that not all patients in the world have similar access to healthcare.