The industry consists of pharmaceutical companies and med-tech companies that have expertise in the development and marketing of new therapies and technologies.
“People ignore design that ignores people” – Frank Chimero
Silver Human Practices
Integrated Human Practices
Model & Wet-Lab
To solve problems that concern humans, the key is to involve all stakeholders that could be affected by our solution as well as the stakeholders that could affect our solution. The involvement of stakeholders is inevitable in all stages of the human-centered design to develop a solution that is good and responsible for the world.1 Involving stakeholders does not just mean you listen to them, but that you strive to understand their values, norms, and needs in order to integrate these into the design of your solution.
To assess whether !MPACT could benefit patients and society, a lot of effort was put into involving all stakeholders during the entire process of our project. To validate the problem and our designed solution, we looked into the societal, technological, entrepreneurial, legal, safety, and ethical considerations of our project together with the stakeholders. This page gives an overview of all Human Practices work. Make sure to click on each link to see how Human Practices benefitted and shaped our project.
On the Integrated Human Practices page you can read how we integrated the input of the different types of stakeholders into our project. The complete Human Practices journey we went through with our partners is discussed through an interactive timeline containing interviews and milestones we achieved. In the end, we explain how we closed the loop between what was designed and what is desired.
To get confirmation whether !MPACT is good and responsible for the world we, together with the iGEM team BOKU Vienna 2022, paid special attention to the danger and risks of our project and synthetic biology. We tried to identify the parties that could be negatively impacted, parties that are firmly against our project, and parties that could use !MPACT for unintended purposes (dual-use). It was both challenging but also inspiring to listen to and discuss with stakeholders who have different opinions than you. To understand their reasoning, we tried to apply the principles of Fran Lewitter from which we learned how to communicate with someone who has a different view on a subject.2 More information about our partnership with iGEM BOKU Vienna 2022 on Human Practices can be found at our Partnership page.
As part of the iGEM community, we value safety a lot. For our Human Practices work, we, therefore, strongly considered safety for the patient, the environment, society, and hospitals, since we believe safety is pivotal if you are at the forefront of new technology. We also tried incorporating safety in our research while conducting Human Practices work. More information about how we made sure to conduct research in a safe and ethically responsible way, can be found on our Safety page.
On the Proposed implementation page it is described how we would implement !MPACT in the real world. Each step along the drug development process from the current research & development phase until the phase of market access is explained with help of the stakeholders we engaged. It is elaborated on the challenges we have to overcome, the safety issues we consider, and who the proposed end-users of !MPACT are.
To commercialize !MPACT, we built a complete business plan together with the help of numerous stakeholders. In this business plan, we explain our target customer, the product, and the potential market. We show multiple analyses and created a financial plan to prove the viability of our business idea. Make sure to not miss out on how Human Practices helped us in shaping our business case on the Entrepreneurship page.
“Stakeholder engagement is a never-ending process. We have to continually earn stakeholders’ confidence. It’s a relationship” – Wouter Vermeulen
Identifying the problem
Value Sensitive Analysis
Reflection & Conclusion
On this page, the problem iGEM team TU Eindhoven 2022 faces about patients suffering from ANCA-associated Vasculitis (AAV) is explained and supported by a patient journey. All relevant stakeholders to this problem are identified through an extensive brainstorming session with the complete HP team. We engaged all stakeholders to understand their values, their needs, their influence on the problem, and the possible influence of !MPACT on them. We created a stakeholder map that positions each stakeholder and shows the flows between them to get a bird’s eye view of the complete situation. Besides, the relevance and priority of each stakeholder are assessed using a power-interest matrix. Next, the values and needs of each stakeholder are translated into design requirements employing a value-sensitive approach also used by iGEM TU Delft 2021. For this, we were also inspired by iGEM LINKS China 2021 who pointed out that; “The core of Human Practices is to show that your project is good and responsible to the world, so the first thing iGEM team should do is to clarify their own values“. Lastly, we reflected on whether our project and our way of conducting research are good and responsible for the world.
Make sure to read the Integrated Human Practices page to learn how we implemented the feedback of stakeholders in our project.
From University Medical Centers (UMCs), doctors, patients, and patient foundations we learned about the negative impact of autoimmune diseases on the lives of the patient as well as on healthcare. Moreover, they acknowledged the problem of insufficient therapies to treat these diseases and confirmed the need for more effective therapies. Currently, 3-5% of the world population is affected by autoimmune diseases and this number is rising.1,2
During the initial idea screening phase of our project, we decided based on the input of our PIs and literature study to investigate a cell therapy based on a Generalized Extracellular Molecule Sensor (GEMS) platform.3 University Medical Centers, hospitals, and pharmaceutical companies advised us to focus on a group of rare, but life-threatening autoimmune diseases named antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) for our designed cell therapy.4 This is a collection of severe chronic disorders characterized by granulomatous and neutrophilic tissue inflammation causing necrosis of blood vessels; mainly small-to-medium vessels.4–6 The necrosis of vessels leads to insufficient oxygen supply to the organs behind the vessels. As a consequence, a decrease in tissue functioning or tissue death occurs.7 Suffering from AAV is experienced as burdensome which is depicted by the patient journey (Figure 1) . This patient journey is composed using the feedback we received from interviews with AAV patients and the Vasculitis Foundation. Three types of AAV are classified; granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA). As GPA is the most common type of AAV, our project focuses on the chronic, systemic, and relapsing disease GPA, formerly called Wegener’s granulomatosis (WG).8 The stakeholders we engaged also advised to focus on this disease because it is the most lethal subtype of AAV, no sufficient treatments are available for it and it is associated with the production of pathogenic disease markers called Anti-Neutrophil Cytoplasm Antibodies (ANCAs). These antibodies target two major antigens: leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO).5 80-90% of the GPA cases have PR3-ANCA, meaning that the autoantibodies, ANCAs, target PR3.8 PR3-ANCA-positive patients are at great risk of getting relapses of the disease, which is why we focused on PR3 for our cell therapy design.7 We also considered other autoimmune diseases such as Multiple Sclerosis (MS) or dermatomyositis, but Maastricht UMC, Novartis, and the Catherina hospital we engaged discouraged these applications because they are not associated with a single pathogenic biomarker that fluctuates with the severity of the disease. Therefore, these diseases would not suit our designed cell therapy. Moreover, since GPA is a rare disease, Novartis explained this could have advantages in terms of competition and market entrance.
The current treatments for AAV are immunosuppressive drugs i.e. drugs that suppress the immune system.9 However as also Maastricht UMC confirmed, 10-30% of the patients do not respond to the current immunosuppressive drugs, 50% of the patients have relapses of the disease after 5 years despite the immunosuppression and the treatment-related toxicity of the immunosuppressive drugs contributes to morbidity and disabilities. Moreover, because of the high healthcare expenditures and workloads, there is a high unmet need for the treatment of AAV.9,10
Figure 1 | Patient Journey. A frequent patient journey AAV patients are going through.10
Considering the initial feedback we received from UMCs Rotterdam, Utrecht, Maastricht, Catherina Hospital, and pharmaceutical company Novartis we designed a Modular Personalized Autoimmune Cell Therapy (!MPACT) that tackles the above-mentioned problems for the AAV patients and hospitals. We started with AAV and more specifically GPA, but eventually, we aim to adjust !MPACT for other autoimmune diseases as it is considered a modular platform technology.12
To get a better understanding of the problem that !MPACT addresses and to learn more about our project, more information can be found on the Project Description page. To learn how we determined together with stakeholders our project idea in detail and to learn how the design of !MPACT is co-created with the stakeholders, definitely check our Integrated Human Practices page.
The industry consists of pharmaceutical companies and med-tech companies that have expertise in the development and marketing of new therapies and technologies.
Academia are universities such as the Technical University of Eindhoven, academic hospitals connected to a university such as University Medical Centers (UMCs), and research groups.
Healthcare consists of hospitals and hospital workers such as doctors and caregivers.
Patients diagnosed with ANCA-associated Vasculitis (AAV).
The sector government comprises governmental organizations and advising bodies to the government. Moreover, we label actors that test activities to the Dutch law and regulations such as lawyers, to the government sector.
Organizations that aim to benefit the general public, the environment, and society at large.
Local organizations, individuals, and the overall society relevant to the development of !MPACT.
A Mendelow’s Matrix (power-interest matrix) is used to manage all stakeholders in the most efficient way and to prioritize the values of the most relevant stakeholders (Figure 5). 13 Therefore, all stakeholders are grouped based on Power (their ability to influence our project and our strategy) and Interest (how interested they are in our project succeeding). For each quadrant, a different action plan is employed on how to manage the respective actors.
The goal for the stakeholders in this quadrant is to manage them closely, meaning we aim to fully engage with these stakeholders through regular meetings and by keeping them constantly informed. With them, we discuss all the choices we make and the progress we book with our project.
For the stakeholders in this quadrant, we aim to keep them satisfied. This means we put enough work into the relationship with them to keep them posted on our main achievements as a team. We try to do this personally via occasional meetings or via mail contact.
The stakeholders that do not have much power but who are very interested in our project we try to inform adequately by mailing them all together our news articles and achievements. Moreover, we support them to follow us on social media such that they do not miss out on our activities.
The goal for this quadrant is only to consider them, meaning we only contact them if we require expertise on a specific topic.
As explained, we strive toward involving society in the engineering design process to meet their needs successfully. We believe that for new technology to be accepted in society, one should listen to, evaluate, and incorporate the voice and the context of the users and society in your design. This is called a consumer-driven product design which has been proven to better fulfill the needs of the user.14 We use a consumer-driven product design by implementing the value-sensitive design (VSD) for !MPACT. This analysis has also been used by iGEM TU Delft 2021. The method allows to proactively consider the human values of all stakeholders throughout the entire engineering design process.15, 16 For every stakeholder that has an influence on the development of !MPACT or vice versa, we deducted and prioritized their values, which we subsequently translated into norms and design requirements. The VSD enables a systematic approach to collect, compare, and process the values of the involved parties to embed them into our new technology. Moreover, it helped us to recognize conflicts between values and to prioritize which values should be integrated into our technology.
The previously identified values per stakeholder (see Figure 4), are condensed to the most relevant values for the design of !MPACT in Figure 6.
These values we derived will drive the design and development of !MPACT by translating them into norms and design requirements. For each of these values, this is represented by a value pyramid. Click on each value to learn more about them!
The mission of our team with !MPACT is to improve the quality of life of AAV patients and therefore contribute to public health. The value Public Health is defined as people with good complete physical, mental and social well-being and not merely the absence of disease or infirmity as stated by WHO (World Health Organization).17 Associated design requirements to the value Public Health are desired by organizations such as a public health organization, Rijksinstituut voor Volksgezondheid en Milieu (RIVM, Dutch National Institute for Public Health and the Environment), European Medicines Agency (EMA), Vasculitis Foundation, Zorginstituut Nederland (national health institute of the Netherlands), and AAV patients. Look at Figure 4 to learn more about these stakeholders.
During our Human Practices work, we have learned that Public Health is in strong conflict with the value Profitability. Several parties such as the EMA and Zorginstituut Nederland explained that with the current technology, there’s much more possible in terms of new therapies. The limiting factor is, however, money. To get the therapies to the market and to get new drugs in health insurance, huge investments are necessary. However, if the development of the therapy is not profitable enough or when the societal support base is not sufficient, the technology will never reach the patient.
Three important aspects of pharmaceutical Quality include effectivity, safety, and reliability.18 The safety is discussed in a separate value pyramid. Effectivity and reliability mean respectively the extent to which a drug achieves its intended effect in the usual clinical setting and a drug that produces similar results in different patients.19 Organizations who contributed to the formulation of the associated design requirements to the value Quality, include the University Medical Centers (UMCs) of Rotterdam, Utrecht, and Maastricht, the Catherina Hospital, the company CiMaas, and pharmaceutical companies such as Novartis and Organon (Figure 4).
Safety measures can be applied for several purposes, so we considered Safety with respect to the user of !MPACT (the patient), the environment, and society. We define safety as a state in which hazards and conditions leading to physical, physiological, and material harm are controlled in order to preserve health and well-being of individuals and the community as stated by the Institut National du Service Public (INSP).20 Measures to ensure the safety of the patient are supported by the University Medical Centers (UMCs) in Rotterdam, Utrecht, and Maastricht, the Catherina hospital, the European Medicines Agency (EMA), pharmaceutical companies Novartis and Organon, the Centre for Human Drug Research (CHDR) and Zorginstituut Nederland (the health institute of the Netherlands). Moreover, the Vasculitis Foundation and the AAV patient value safety for the patient a lot as well. In addition, organizations such as the institute for public health and environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM) and the independent environmental organization Greenpeace, gave us new insights into safety measures to protect the environment. Lastly, we discussed with Lawyers, the Vereniging Innovatieve Geneesmiddelen (VIG, association of innovative medicine), KU Leuven, and dr. Koos van der Bruggen, the risks of our project for society and the dual-use of !MPACT. Look at Figure 4 for more information on these stakeholders.
Medical innovation is defined by the WIPO (World Intellectual Property Organizations) as increasing knowledge and transforming existing processes and business models to better serve to change needs and expectations.21 Therefore, !MPACT should either focus on a new application (disease) and/or should be based on new technology. Inherent to innovation is protecting your new technology. We discussed the possibilities for protecting !MPACT with The Gate, a supporting organization for enterprising researchers and students at our university. The University Medical Centers (UMCs) in Rotterdam, Utrecht and Maastricht and the Catherina Hospital helped search for the best application (disease) of !MPACT. Look at Figure 4 for more information on these stakeholders.
Efficiency measures whether healthcare resources are being used to get the best value of money.22 Efficiency is thus important for the production process of !MPACT but also for the operations of the iGEM TU Eindhoven 2022 team. Johnson &Johnson, leading company in the pharmaceutical industry, thought us the importance of efficiency during the production of !MPACT and they elaborated on the production facilities required for efficient production. TMC, a high-tech consultancy company, helped our team operate as efficiently as possible to increase the success of our project and our team. Look at Figure 4 for more information on these stakeholders.
The design requirements related to Efficiency are in conflict with the design requirements deducted from Quality. Fulfilling all quality design requirements increases the complexity of the cell therapy that in its turn increases the number of production steps of !MPACT. In the same way, the Safety design requirements could be interfering with the design requirements related to Quality. For example, involving a system to inhibit the cell therapy !MPACT on demand by external stimuli could decrease the efficiency of the production process.
We define profitability just like W. Edwards as the degree to which the value of a company’s production exceeds the costs of the resources used to produce it. Companies Novartis, ThermoFisher, Organon, BOM, and a support center for enterprising researchers and students, the Gate helped us to define the requirements needed to build a successful and profitable start-up out of our project. A very important step in this process was validating the demand for !MPACT. We tried to validate the demand based on three different perspectives by involving University Medical Centers and hospitals, patients, and Zorginstituut Nederland (Figure 4).
Just like efficiency, also Profitability can be conflicting with the Quality of !MPACT. One of the requirements for a profitable organization is to minimize production costs. However, a cell therapy that is very complex compared to average drugs, is also more costly. A more expensive therapy again also has an influence on its incorporation into health insurance. When designing a new cell therapy like !MPACT, it is thus critical to take these requirements into account as well, since they also determine the success of your new therapy.
We value, just like the overall iGEM community, integrity, honesty, and trustworthiness a lot. Integrity is defined as having strong moral principles and being honest. As a result, we have put extra emphasis on integrating this value into our own team together with the Ethical Review Board of our university. Moreover, we tried to follow the ethical and legal guidelines pharmaceutical companies follow with respect to publishing and marketing their new drugs and therapies. These guidelines are essential for responsible implementation of !MPACT.
We have learned that Communication is crucial in the field of synthetic biology. In our partnership with iGEM BOKU Vienna, we discovered that the knowledge of synthetic biology among the general public is limited. For more information on this partnership, please visit our partnership page. With the help of the Vereniging Innovatieve Geneesmiddelen (the association of innovative medicine, VIG), dr. Koos van der Bruggen, Lawyers, Greenpeace, the Rijksinstituut voor Volksgezondheid en Milieu (RIVM, institute for public health and environment), European medicines Agency (EMA), and Zorginstituut Nederland (the national health institute in the Netherlands) we have discussed how to communicate to different target audiences and how information is conveyed properly. In addition, the bottlenecks of current policies on communication around synthetic biology are identified and strategies on how to improve this communication are suggested. Literature states that first of all the scope of synthetic biology needs to be universally defined since multiple definitions lead to indistinctness. Secondly, the way discoveries in synthetic biology are owned and shared should be improved. Lastly, more investment is required in the communication of synthetic biology issues to the general public.23 The design requirements derived for Communication are in line with the design requirements of Integrity. Information should not only be communicated to the right target audience in a clear and understandable way, but the information itself should also be honest and objective.
Privacy is an important part of doing ethical responsible and integer research. Data Privacy can be defined as the intention to keep personal data safe against improper access, theft, or loss.24 As a consequence of digitalization, information privacy has regularly featured as a topic in the news, media, and has grown into a complex legal subject. As a propagator of iGEM, we put the safety and interests of our partners first. Together with a data steward from our university, we defined the requirements necessary to ensure the privacy of all involved actors in our iGEM project and to follow the GDPR guidelines. Just like the Communication design requirements, also the requirements related to Privacy are in line with Integrity.
We discovered that for a project that is good and responsible for the world, you should always consider a balance. It became apparent during the value-sensitive analysis that different stakeholders have different values leading to different design requirements. These design requirements can be in conflict and the goal is to meet the design requirements of all involved actors in such a way that the benefits for them are larger than the costs. We have learned that you can never completely fulfill the needs and interests of each stakeholder, so you should prioritize which stakeholders, values, and design requirements are most important (e.g. by use of a power-interest grid) and try to fulfill the needs in such a way that all stakeholders are satisfied. This balance is something everybody in the iGEM community should keep in mind when they involve stakeholders in their project design. Future iGEM teams should not try to meet all design requirements, rather they should prioritize the requirements and try to satisfy the most relevant stakeholders first.
At the very beginning of this iGEM year, we started with the ambition to create a meaningful and responsible project that has an impact on the world and local communities. For this, we involved stakeholders from as many areas/backgrounds as possible. For each sector, we validated our ambition based on the literature research, analyses, and stakeholder interviews we performed. Combining these different methods resulted in more relevant insights and we therefore also recommend this for future iGEM teams. The potential and the challenges of our project according to each sector are summarized here:
- !MPACT is an innovative promising therapy for a niche market that is currently unmet.
- !MPACT has a resemblance with CAR-T cell therapies which facilitates both the production of !MPACT and filing licenses since the resources are already available and optimized.
- Viable business plan by aiming for an orphan drug label and by targeting a niche market.
- It is possible to patent !MPACT since it is a new and innovative concept that elaborates on existing technology.
- Since !MPACT is based on platform technology, in the future, it could be used to treat other autoimmune diseases and meet a larger market.
- High investment costs are required for developing, producing, and testing !MPACT in clinical trials.
- A positive benefit-cost analysis is required for !MPACT to get incorporated in health insurance. Therefore, benefits for the patient in terms of more “high-quality years of life" are needed.
- !MPACT has to be significantly more effective and less invasive for the patient to outperform the current therapies for ANCA-associated Vasculitis.
- If you disclose your project (without non-disclosure agreements) it is not patentable anymore.
- You need clinical phase IIa evidence to successfully sell a license of !MPACT to large pharmaceutical companies.
- ATMPs and cell therapies are upcoming for many applications (diseases).
- IL-10 is a promising anti-inflammatory cytokine as a treatment for several autoimmune diseases.
- A GEMS receptor would be a very powerful tool to couple the input to the output of a cell and could be used as a therapy platform for multiple diseases.
- !MPACT is a personalized therapy that adjusts its IL-10 production to the concentration of ANCAs, which is expected to result in fewer side effects for the patient.
- It is important that the modified cells of !MPACT remain in the body for a long time (e.g. memory cells) and can readily be activated such that it can prevent relapses of AAV.
- The cell therapy should be designed in such a way that the cell therapy acts locally at the site of inflammation so that side effects for the patient will be minimized.
- The efficacy of a larger concentration of IL-10 in AAV patients is not yet proven to decrease inflammation and thus requires more research.
- The sensitivity and the activity of the cell therapy !MPACT to the ANCA concentration should be well-calibrated and controllable.
- It would be even better if you could intervene at the cause of the disease (e.g. targeting B cells).
- There is a clinical need for more effective and less burdensome therapies for AAV.
- The immense workloads of hospitals at this moment would be reduced by the one-time treatment of !MPACT compared to the current, time-consuming treatment procedures.
- !MPACT aims to prevent relapses of AAV which is beneficial for the quality of life of patients.
- !MPACT aims to reduce the side effect of a treatment since the immune system is not constantly suppressed. Besides, it is expected to be less burdensome for the patient, as it is a one-time treatment.
- Hospitals should have the licenses and the expertise to administer cell therapies legally and successfully.
- Vein-to-vein time should be minimized in order to treat AAV patients in time.
- Safety of the administered cell therapy for the patient in the long and short term should be validated. The system should be inhibitable by an external stimulus.
- Not all AAV patients are ANCA positive and not all of them have ANCA concentrations that fluctuate with the severity of the disease. Consequently, !MPACT will not be an effective treatment for all AAV patients.
Local communities & patients
- Patients diagnosed with AAV confirm the burdensome side effects associated with current therapies against AAV. !MPACT is expected to be less burdensome for the patient.
- Patients diagnosed with AAV would be willing to receive the cell therapy !MPACT if it is proven to be effective, even if some side effects occur.
- Make the general public more aware of synthetic biology, its dangers, and possibilities.
- The analogy of !MPACT to CAR-T cell therapies facilitates obtaining a license for performing clinical trials and a license for the use of !MPACT outside the lab.
- iGEM TU Eindhoven considers the safety of the therapy from multiple perspectives such as from patient, hospital, societal, and environmental perspectives.
- Many licenses are necessary, for example, to work with GMOs in the lab, the use of GMOs outside the lab, a license for clinical trials, market authorization, import and export licenses, etc. Many licenses require evidence that the therapy is safe and effective.
- Partners you work with should also be qualified and should have the required licenses.
- All countries have different laws and regulations which require different strategies for market entrance.
- Reimbursement of !MPACT is vital to successful market access and requires a positive cost-benefit analysis.
- The communication guidelines iGEM TU Eindhoven aims to follow are effective and ethically responsible. Communication about !MPACT and the results are honest and transparent.
- It is good that iGEM TU Eindhoven communicates to multiple stakeholders such as experts, healthcare insurers, society, and AAV patients.
- iGEM TU Eindhoven takes into account the target audience to whom they are communicating.
- iGEM TU Eindhoven involves patients in the development of new medicine to validate the need for a new therapy as well as the desirability of the solution among the end-users.
- Elaborate ethical considerations (e.g. dual use) are discussed.
- Although !MPACT is expected to be very expensive and at first will not be available in all countries, as with most new technology in healthcare, it will become cheaper and eventually will be reimbursed by more countries.
- Make more experts (doctors, hospitals, and research institutes) as well as society aware of AAV.
- Misconceptions about synthetic biology should be prevented and taken away. This can be achieved by good and transparent communication.
- The awareness among life scientists about the possible misuse of the research results is still limited and should be improved. Institutional organization of biosecurity regulation is required.
- A cell therapy for rare diseases like AAV will probably not enter the market in many countries, possibly contributing to inequalities in healthcare between countries.
All sectors see potential in !MPACT and believe that we can overcome the challenges. They agreed that our project is responsible for the world for which evidence can be found on the Integrated Human Practices page. On that page, all interviews with stakeholders are processed and it is shown how we integrate their feedback in our project. In conclusion, together with stakeholders we designed !MPACT that will benefit the world in a responsible way since our project will improve the quality of life of ANCA-associated Vasculitis patients while at the same time safety for the patient, society, and environment is taken into account. In addition, the risks, dangers, and negatively affected people are considered when designing !MPACT. Moreover, it is proven the business plan for !MPACT is viable (Entrepreneurship), the proposed implementation for !MPACT in the real world is realistic (Proposed implementation), and we communicate honestly and transparently about our project.
All our team members are trained as hardcore scientists and engineers; therefore, we first underestimated the necessity of human practices work and the richness of information you get when you involve stakeholders and the real world in the project. During the human practices work we realized how much we could learn from involved actors and experts in the field and how much they could change our perspective on the project. Involving stakeholders early in the project helps to validate the problem and the need as well as find a desirable and feasible solution. This journey has surprised us with lessons and discoveries summarized in a sentence cloud (Figure 8).
"Human Practices is the study of how your work affects the world, and how the world affects your work" – Peter Carr, Director of Judging
Close the feedback loop
Stakeholder's critical view of our ideas and their feedback helped us to optimize our project plan and solution design into one that is effective, feasible, and likely to be successful in each sector. Integrating feedback, values, and needs of relevant stakeholders is important because engineers and entrepreneurs tend to fall in love with their initial design or invention. This results in blindness to useful feedback and criticism from users and stakeholders. A massive 96% of dissatisfied customers won’t complain directly to the company but they will tell 15 other people about their bad experience.1 It is our job to engage with stakeholders, be open to feedback and integrate feedback, to be successful.
The development of a cell-based therapy is a time-consuming process that consists of multiple phases. It starts with the R&D phase followed by securing IP, preclinical and clinical tests, production, legislation, and marketing. To understand the complete process of implementation and to be able to integrate the requirements of every phase for the design of our cell therapy, we have consulted experts in six main fields; the need, the science, implementation, safety & ethics, laws & regulations, and business. Each field contributes to the problem and our solution from a different perspective, thereby leading to distinctive requirements for both our project plan and our solution design. We, therefore, bring together all sectors to make an impact on society, while at the same time we are being responsible and good for the world. To ensure we do not fall in love with our initial design, !MPACT is engineered through a human-centered design at every stage. For more information on which tools we use, open the sections below about the AREA framework and the Gibbs reflection cycle.
The business experts help us make a viable business of !MPACT by creating a strong business plan. Moreover, they give feedback on how we can best legally protect our new invention.
The experts we engaged with to understand how !MPACT could enter the real world. This covers the entire process from the R&D phase followed by securing IP, preclinical and clinical tests, production, legislation, and marketing until !MPACT reaches the end-users.
Specialists in the field of safety of new genetically modified organisms (GMOs) and the ethical discussions around GMOs. Based on their feedback, we would like to make a safer and more ethical responsible design.
The experts that have relevant expertise on the technology behind !MPACT. Via them, we would like to gain feedback on how to improve the technology to make !MPACT more effective, safer, and cheaper to produce.
LAWS & REGULATIONS
Experts who have expertise in the laws and regulations of medicine that utilize GMOs. They have crucial knowledge on how to develop a legal therapy and how to implement this in the real world in a legitimate manner.
Experts that we engaged to verify the problem we outlined and to validate the need for a new therapy such as !MPACT from multiple points of view, including clinical perspective, patient perspective, and societal perspective.
Closing the feedback loops of engagements with relevant stakeholders is key to integrating human practices. We used a structured and iterative tool called the AREA framework to integrate the feedback we received from stakeholders in our project. The AREA framework is a powerful tool that addresses social and ethical concerns and is used by many research institutes.2 This method, created by Professor Richard Owen, was optimized and implemented by iGEM Team Exeter 2019. We optimized the AREA framework even further for our purpose to integrate the feedback we received from stakeholders and closing the feedback loops. This method uses, just like the method from iGEM Team Exeter 2019, four steps of the AREA framework as a guide to how we integrated and processed the discussions with all stakeholders. Click on each section of the AREA framework in the section below to learn more about each phase and look at how we used the AREA framework to process the received feedback.
Next to the AREA framework, we used a reflection tool to reflect on all the feedback and information gathered from different stakeholders to prioritize requirements and make well-informed decisions. These decisions shaped our project. Therefore, they are considered milestones we achieved during the design process. The reflection tool used is based on the Gibbs Reflective Cycle and functions as a useful extension of the AREA frameworks. We altered the Gibbs Reflective Cycle in such a way that applies to the choices and challenges we faced during our project (Figure 1). The Gibbs Reflective Cycle has been found to help people think clearly and systematically about learning situations. It encourages people to get a better understanding of the experience and teaches them how to improve next time.3 Therefore, we encourage iGEM teams in the future to use a combination of AREA frameworks and the Gibbs Reflective cycle to enable a systematic reflection on both discussions with stakeholders as well as decisions made by the team.
The interactive timeline tells the story of how the engagement with stakeholders shaped our project plan and solution design. It ties together all of our human practices efforts to make sure !MPACT will have a large and responsible impact on all the defined fields; the need, the science, implementation, safety & ethics, laws & regulations, and business. In addition, it explains the learning process of how !MPACT should be implemented in the real world.
The rectangular text boxes show the iterative (AREA) feedback loops and the circular boxes show the (Gibbs) reflection points with the corresponding milestones. Make sure to click on both of them to travel along our complete journey. The AREA feedback loops have flag markers with different colors in the top right corner to indicate for which field we engaged the respective stakeholder. An example of an AREA framework with an explanation of its structure is given below. If you only wish to get the highlights of our Human Practices journey, we advise reading the take home messages of each conversation and the milestones/reflections.
Prof. Dr. Ir. Luc Brunsveld
Prof. Dr. Maarten Merkx
Prof. Dr. Ir. Tom de Greef
Eindhoven University of Technology
Based on the discussion with our PIs, we decided to do literature studies into three topics including the GEMS-based system (Generalized Extracellular Molecule Sensor platform), an exosomal miRNA diagnostic tool, and a design that stimulates bacterial cell death as an alternative to antibiotics.
Prof. Dr. Ir. Luc Brunsveld
Prof. Dr. Maarten Merx
Prof. Dr. Ir. Tom de Greef
Post Doc Alexander Gräwe
Eindhoven University of Technology
After the second meeting with the PIs, 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.
Dr. Henny Otten
Dr. Jorg van Loosdregt
prof. Dr. Femke van Wijk
Utrecht University Medical Center
Based on the feedback of Utrecht UMC on our project that makes use of the GEMS receptor, we considered other autoimmune diseases we could target than Multiple Sclerosis (MS) such as dermatomyositis. Moreover, we reviewed the suggestion to implement interleukin-10 (IL-10) as the output of our cell therapy.
Dr. Joyce Curvers
We got useful suggestions to look into other auto-immune diseases such as vasculitis and we got encouraged to review the viability of "decoy" receptors as output of our engineered cells.
Mark van Hattum
Also, Novartis had doubts on treating MS with !MPACT and they suggested using IL-10 as output of our cell therapy as well. Moreover, the meeting with Novartis triggered us to start working on a business model and the implementation of our cell therapy !MPACT.
Jonathan Fajardo Cortes
The BOM had critical notes on using "decoy" receptors in our design for !MPACT. Moreover, due to the discussion with the BOM we started doing literature research on which immune cell type would suitable to harvest from the patient for the proposed implementation of !MPACT.
ThermoFisher Scientific helped us to quantify our business plan. With input of ThermoFisher Scientific we elaborated on our cost structure and revenue stream.
Organon missed the implementation of our therapy and encouraged us to think about each step of the drug development process. Moreover, dividing the implementation process of !MPACT into distinct phases helped us to make more reasonable assumptions on the cost structure for our business plan.
Dr. Joyce Curvers
From the meeting with dr. Joyce Curvers we learned that our proposed project idea, focused on dermatomyositis was not feasible and not sufficiently desirable. Therefore, we decided to again do literature studies on a better alternative disease for !MPACT.
TMC helped us to convey our message to different target audiences in an understandable way. Based on their advice we created three different project presentations ranging in complexity for different stakeholders we engage.
Dr. Jan Damoiseaux
Dr. Jan Damoiseaux agreed with dr. Joyce Curvers that dermatomyositis was not suitable for the design of !MPACT and he encouraged switching to another autoimmune disease such as anti-neutrophil cytoplasmic antibody (ANCA)-associated Vasculitis (AAV). Based on this feedback we decided to investigate AAV as the disease to target with !MPACT.
Dr. Marco Schreurs
Dr. Hanna IJspeert
Dr. Wim Dik
Erasmus Medical Center
Next to Dr. Jan Damoiseaux and dr. Joyce Curvers also Erasmus MC advised us to choose another disease. They suggested focusing on Graves' disease. Based on all feedback we collected, we planned to discuss the pros and cons of each suggestion to make a well-grounded decision for the disease we want to treat.
Organon helped us improve our business model by elaborating on our SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis and financial plan. Furthermore, they advised us to approach a cell therapy manufacturer.
Mark van Hattum
Albert van Hell
Novartis critically reflected on our value proposition and offered suggestions for a price estimation of !MPACT. They encouraged us to determine the AAV population size and to engage an immunologist to discuss the localization of !MPACT in the human body.
Mark van Hattum
After we pitched our project in one minute to Novartis, we learned how to improve our unique selling point and define our team's mission. Our improved mission is to design a cell-based therapeutic for autoimmune diseases, starting with AAV.
Dr. Matthias Busch
Maastricht University Medical Center
During the meeting with Matthias Busch we learned about the current treatments of AAV, and the advantages that our solution !MPACT has to offer. Moreover, we gained more insights into the need for improved therapy to treat AAV from a clinical point of view. Based on these new insights we formulated clear selling points of our solution.
Dr. Jolanda Habraken
Ethical Review Board TU/e
The Ethical Review Board of our institution helped us to act responsibly with the (personal) information we obtain from stakeholders. We made informed consent forms for the participants and filed for institutional approval for our Human Practices research.
Dr. ir. Cecile van der Vlugt-Bergmans
We got aware of more safety issues affecting our project such as safety during cell therapy production, safety for the environment, long-term consequences for human health, and safety during the administration of !MPACT. We got encouraged by the RIVM to meet more stakeholders to discuss safety & ethics of !MPACT.
Liesbeth Varion (BSO)
Eindhoven University of Technology
With the BioSafety Officer of our institution, we discussed all experiments we planned for our project. We implemented necessary safety precautions into the experimental protocols to make sure we work in a sterile environment to protect ourselves, the experiment, and the environment.
Peter made us aware of how patients experience AAV and what the needs of the patient are concerning new therapies. He also helped us to come in contact with AAV patients.
TU/e (Data Management and Library)
Anne learned us how we should gather, handle, process and store the data of the participants for our Human Practices responsibly.
The gate learned which steps we must take to legally protect !MPACT after the Grand Jamboree. They learned us how to file a patent and how to make sure our project does not gets disclosed after the Grand Jamboree.
Koosje van Lessen-Kloeke
Life sciences and Healthcare lawyer
Koosje van Lessen-Kloeke made us aware of the laws and regulations during the complete drug development process for !MPACT which we integrated into the proposed implementation of our project.
Dr. Wilfred Germeraad
CiMaas proposed to "harvest" B cells from the patient as immune cells to use for the implemented production of !MPACT. Consequently, we got encouraged to do a literature study on which cells should be harvested from the patient for the proposed implementation. Moreover, CiMaas helped us to determine the milestones for our business plan.
Dr. Marjolein van der Poel
Maastricht University Medical Center
Dr. Marjolein van der Poel taught us the safety issues during the administration of cell therapies and she mentioned the common side effects. Furthermore, she noted some challenges we should overcome such as a way to control IL-10 production of our cell therapy.
Dr. Jeroen van Smeden
The CHDR showed us how clinical trials are conducted and they elaborated on the details of clinical trials for cell therapies. We used this information for the proposed implementation. In addition, they explained the associated costs of clinical trials that we integrated in our business plan.
Johnson&Johnson explained safety measures we must be aware of during scaled-out production of !MPACT. They also explained the production process of cell therapies and the associated challenges which are integrated into the proposed implementation. Lastly, they verified the possibility for up-scaling of the production of !MPACT.
Peter Bertens taught us we should communicate our project in a transparent, simple and targeted way. The VIG also stressed the importance of reimbursement for !MPACT if we want to reach the patients eventually.
Dr. Sc Mauritz Kelchtermans
Mauritz Kelchtermans learned us more about the differences in regulations concerning GMO's in Europe and the US. He gave his opinion on the use of GMOs in society and explained how we should communicate to prevent misconceptions, which we integrated in the proposed implementation and the operations of us as a team.
Prof. Reno Debets
Erasmus Medical Center
Reno Debets elaborated just like CiMaas on which cell type we should harvest from patients to produce !MPACT. He advised using T cells instead of B cells. Consequently, we again delved into the literature to state the pros and cons of both possibilities. We integrated this assessment into the proposed implementation.
Dr. Koos van der Bruggen
ex-Rathenau institute, ex-KNAW
Koos taught us the risks of dual-use of our synthetic biology and our project and explained which measures we should take to prevent misuse of !MPACT. We implemented these measures in our research and from now on act in accordance with the Dutch Code of Conduct for Biosecurity.
Interviews with the AAV patients motivated us, even more, to work on our project. Moreover, they clearly explained their need. Based on these insights we prioritized which design requirements of !MPACT are most important.
Dr. Barbara te Riet-Schulte
Dr. ir. Cecile van der Vlugt-Bergman
During the second meeting with the RIVM we reflected upon all safety considerations we delved into. Moreover, they explained us the risks of !MPACT for the environment and suggested some challenges we should look into such a way to inhibit or control the IL-10 production of !MPACT.
Zorginstituut Nederland (National Healthcare Institute)
Noraly stressed the importance for !MPACT to be reimbursed in the basic package of health insurance for its success. She explained the process of reimbursement and the role of Zorginstituut Nederland (National Healthcare) institute in this process, which we integrated in our business plan.
Regulatory Science Network Netherlands
Bert Leufkens explained the market authorization process of new drugs and the special issues during this process for cell therapies. We integrated market authorization in our proposed implementation.
dr. Kevin Stairs
Kevin Stairs from Greenpeace described the risks of GMOs for the environment and explained how proper risk assessment is performed. We integrated this in the proposed implementation of !MPACT.
Public health organization
The public health organization explained the cause of inequality in access to healthcare and they predicted that !MPACT would not be offered in each country. They explained which measures we can take to equal access to !MPACT and they explained why it is important anyway that innovations take place. We integrated this discussion in the proposed implementation of our project.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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?
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
We will wait for approval of our informed consent forms, our PIA proposal and our research project proposal.
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.
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.
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.
Our team decided to keep the possibility of a patenting application in mind for after the Grand Jamboree.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
We will investigate the regulations for orphan medicines and their benefits based on the advice of Bert Leufkens.
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”.
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.
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.
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.
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.
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.
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.
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.
We started our iGEM project with extensive literature research, brainstorming with our team, and meetings with our PIs to decide what project we want to focus on in the iGEM competition. Our challenge was to decide which topic would be the focus of our project. This topic should be feasible for the development of a realistic and original proof of concept based on synthetic biology.
All members of our team were very enthusiastic about the three potential project topics we had in mind. Because of this, we were extremely motivated to perform research on these topics. On the other hand, we thought it was difficult to decide since it was an important choice that would determine the foundation of our project.
To make a well-considered choice, we divided our team into three subgroups. Dividing the teams into subgroups helped us to effectively gain information about multiple topics. The findings were summarized in a clear presentation, which we pitched to our PIs and instructors. After this pitch, we received useful feedback and gained new insights that clarified which topics had the potential to develop a feasible and desirable project.
Based on the feedback that we received, we discussed the different project ideas and listed their pros and cons. After this, we concluded that a cell therapy based on the GEMS (Generalized Extracellular Molecule Sensor platform) system would be the most feasible project to develop for this competition because this project idea is clearly related to synbio. Moreover, this topic fits the expertise at our university most.
Our next step is to decide which autoimmune disease we want to focus on with the design of our cell therapy. To do this, we are planning to divide our team into subgroups again to extensively perform literature studies into different auto-immune diseases and their corresponding biomarkers.
After two meetings with our PI’s, extensive literature research, and many brainstorming sessions with our team, we decided to continue with a cell therapy that makes use of the GEMS (Generalized Extracellular Molecule Sensor ) receptor and “decoy” receptors. Since we started reasoning from our in-house technology, the challenge we faced was finding a suitable disease for which our cell therapy could be used. The PI’s encouraged us to investigate well-known antibody-antigen combinations that are commercially available and could be implemented in a proof of concept of our cell therapy.
In the beginning, the task of finding a suitable disease for our designed cell therapy felt like a mission impossible. Firstly, there are so many autoimmune diseases that each express multiple associated auto-antibodies. In addition, we also considered other diseases that were correlated to the overproduction of specific biomarkers. As a result, we were overwhelmed by the numerous possibilities.
To overview the possibilities, we decided to split up our team into four groups of two. Three groups were supposed to look into four different auto-immune diseases and their corresponding autoantibodies. One group was supposed to investigate other types of diseases that could be suitable for our cell therapy. All subgroups performed an extensive literature study and summarized the findings in a clear presentation. Subsequently, each group pitched their findings to the rest of the team. From this, we learned that structurally dividing the work and initially brainstorming in smaller groups, leads to much more efficiency. Moreover, we were able to create an overview of potential diseases that was much better manageable.
After we discussed the possibilities, we concluded that Multiple Sclerosis (MS) was the best fit for our cell therapy. In MS, many autoantibodies are produced and there is a large overlap between patients with regard to the presence of specific autoantibodies. In addition, MS has a high prevalence and mortality rate. Furthermore, no efficient therapies for MS are available yet.
Now, we have our project idea and the disease we want to focus on with our designed cell therapy called !MPACT. The next step is to reach out to experts in autoimmune diseases and immunology to validate the need for our innovative cell therapy and its underlying science.
After the decision to focus on MS, we verified our cell therapy !MPACT for treating MS with several stakeholders. During interviews with UMC Utrecht, Catharina Hospital, and Novartis we discussed the feasibility of (multiple sclerosis (MS) in our project. All stakeholders expressed concerns regarding the choice of disease. According to them, focusing on a rarer disease instead, with a high morbidity rate and with no efficient treatment available, would offer more possibilities. Small steps in developing an efficient therapy would already lead to a significant impact. Moreover, a rare autoimmune disease would increase the desirability of our treatment. Besides this, it was advised to focus on autoimmune diseases with well-defined disease markers. UMC Utrecht proposed the autoimmune disease dermatomyositis as a disease that could be treated with !MPACT.
Because we found it a hard task to decide which disease would be the target disease of our project, we were relieved after our choice to focus on MS. Therefore, the feedback on our project felt like a setback. Nevertheless, we also saw an opportunity. UMC Utrecht, the Catharina Hospital, and Novartis gave us useful advice, which would make it easier to decide which disease should be the target of our project.
Since UMC Utrecht proposed dermatomyositis, a few team members of our team performed an extensive literature study on this disease. The findings were summarized in a clear presentation that was subsequently presented to the whole team. From this, we learned that it is not necessary to perform specific tasks with the entire team, as long as findings and outcomes are communicated and explained well among the team.
The literature study showed us that dermatomyositis is a better fit for our project than MS. This autoimmune disease is rare, is currently hard to treat, and has a high morbidity rate. In addition, dermatomyositis is characterized by the well-defined autoantibody anti-MDA5. Hence, our team decided to focus on treating dermatomyositis using !MPACT instead of MS.
During our meeting with Catharina Hospital, we were advised to validate the feasibility of the target disease with multiple medical centers and experts. Therefore, our next step is to arrange several meetings with such stakeholders to discuss the design of !MPACT that makes use of “decoy” receptors. Furthermore, we are planning to validate the business viability of our project with pharmaceutical companies and other experts such as the BOM (Brabant Development Agency).
Our proposal to implement “decoy” receptors in the design of our cell therapy caused many concerns among the experts from Utrecht UMC, Catharina Hospital, Novartis, and BOM (Brabant Development Agency). For instance, catching autoantibodies with decoy receptors would not result in suppression of the autoimmune reaction, but only in reduction of circulating pathogenic autoantibodies. Therefore, this proposal would be less effective than current treatments. In addition, it was not certain if activation of the GEMS (Generalized extracellular molecule sensor) system would lead to sufficient decoy receptors placed on the cell membrane. In addition, the question is if these receptors would be capable of capturing enough autoantibodies to reduce the concentration in the blood. Therefore, decoy receptor expression as the output of the activated GEMS system would not be a very effective therapeutic agent to treat autoimmune diseases. Consequently, we decided that we should reconsider the therapeutic agent of our cell therapy design.
Our team was very determined to reconsider the output of the GEMS system. The concerns and arguments that were given by the stakeholders taught us that the decoy receptors would not lead to an effective, improved therapy to treat autoimmune diseases. Therefore, we were determined to improve the design of our cell therapy to increase its value and effectiveness.
To learn more about IL-10 and to investigate if it would be a suitable output for our therapy, we delved into the literature. Furthermore, we proposed the suggestion of Utrecht UMC to consider IL-10 as a therapeutic agent also to Novartis. By proposing the idea of one stakeholder to another, we could validate if the suggestion of Utrecht UMC would be supported by more experts in the field. From this, we gained useful information that helped us to reconsider the design of the cell therapy !MPACT.
Our literature study and the interview with Novartis supported the proposal of Utrecht UMC to focus on IL-10 secretion instead of the expression of decoy receptors. IL-10 is a natural anti-inflammatory cytokine that has been proven to reduce inflammation in multiple auto-immune diseases (Project Description). IL-10 as a therapeutic agent of the cell therapy would suppress the immune system once autoantibodies are present (during disease activity) and interact with the engineered cells. We will therefore implement IL-10 as output in the design of our cell therapy !MPACT.
After this, we will reach out to stakeholders such that we can validate the disease dermatomyositis we aim to target with !MPACT. Also, we will contact more stakeholders that can teach us how to set up a business plan such as ThermoFisher Scientific and Organon.
About a month ago we switched the disease we aim to target with !MPACT from MS to dermatomyositis. We switched because for MS multiple autoantibodies are known, which makes the disease less suitable for our technology. For dermatomyositis on the other hand there is a specific autoantibody known. We validated this pivot with several stakeholders. However, after some more meetings with stakeholders such as Maastricht UMC, Catherina hospital, and Erasmus MC we noticed some drawbacks for dermatomyositis as a target of our cell therapy.
The realization that there are also drawbacks to dermatomyositis as a disease to treat with !MPACT felt like a big disappointment. Especially because we validated dermatomyositis with multiple stakeholders, we performed many hours of literature research, we already started with plans for the lab based on dermatomyositis, and we promoted dermatomyositis everywhere. On the other hand, we felt that we had to move on because we did not have limitless time to spend on the ideation phase of our project. Nevertheless, we were aware that critically reflecting on our project is of great importance and pivoting is necessary in order to create a good project.
We got two suggestions for other more appropriate target diseases, namely AAV and Grave's disease. After the meetings, we performed in-depth literature research on AAV and Grave's disease and checked for both diseases whether they meet all requirements for the design. Finally, we made an overview of the different possibilities for the disease and discussed this with the complete team. In our opinion, the main requirement of our cell therapy is that it should respond to the relapses of an autoimmune disease. In this way, the treatment will be preventive, and it will reduce side effects.
The discussions with stakeholders and literature research showed that AAV has a comparable severity to dermatomyositis, however, its prevalence is higher, and it is characterized by pathogenic autoantibodies that fluctuate along with relapses of the disease. Grave’s disease would meet the main requirement as well, however, the need for novel treatments is low since current treatments are quite effective already. The only drawback for AAV that we could envision was that it is a systemic autoimmune disease, so targeting the disease locally would be challenging. This is thus something we should consider for the outlook of our therapy.
AAV meets almost all requirements of our design, including the main requirement. The only aspect of this disease that is challenging is that it is a systemic disease. A non-systemic disease is preferred above a systemic disease; however, it is no hard requirement in our opinion. We also think that it is more important to choose a disease for which there are currently no appropriate treatments available, than a disease that is not systemic. Therefore, we changed the disease we aim to treat with !MPACT to AAV.
In the next step, we will adjust all promotion material and announce that our project focuses on AAV. We concluded that, at this point, we have discussed the disease we want to target with enough relevant stakeholders, we have clearly defined the requirements the disease has to fulfill and we have made a well-grounded choice for AAV. We will move on to the next topics to cover in our project, like the business plan of our project.
To develop a business plan for !MPACT we must clearly define our final product and how to sell it. We engaged with Novartis, ThermoFisher Scientific, and Organon, to obtain insights into our business strategy. We wanted to learn from them how to go from our proof of concept, which we realized during the iGEM competition, to a viable business case.
Before meeting the experts, our team did not have much knowledge and experience in entrepreneurship. Consequently, we felt hesitant to build a viable business case ourselves. Therefore, we reached out to stakeholders that were willing to help us herewith.
We reflected upon the information received from the stakeholder interviews and discussed this within the team. In addition, we received guidance from the TU/e Contest (Communication) about creating a business plan. The TU/e Contest is a competition within our university that gives engineers the opportunity to further develop their own, ingenious ideas, prototypes, and research projects into business ideas. During this competition, we were guided by several companies. With them, we discussed our business plan to follow up on the stakeholder meetings. The contest was an enjoyable way to get to know the ins and outs of new venture creation at a fast pace.
The meetings with pharmaceutical companies and the discussions with other experts in the field of patenting and new venture creation taught us the innovativeness of our project: its modularity. !MPACT is based on platform technology that can be used for treating multiple autoimmune diseases. Therefore, we decided to license a patent for the proof of concept of our therapy against AAV to our primary customers (pharmaceutical companies). Thereafter, !MPACT can be adjusted such that it addresses another autoimmune disease for which we can again license the proof of concept to a pharmaceutical company. This platform technology of !MPACT could serve as a strong foundation for our business case.
After the TU/e contest, we will continue with our business plan, in which we will elaborate on our value proposition, patenting opportunities, market analysis, commercialization strategy, financial analysis and many more.
During previous meetings with Organon, TMC, RIVM and Novartis, we demonstrated the concept of our therapy to treat AAV. Although all stakeholders saw potential in our project, they noted that it was unclear what the implementation of our project would look like. Overall, the next steps beyond the development of the proof of concept in the lab, were missing. Therefore, their main feedback was that we should start elaborating on how our engineered cells would eventually lead to a therapy that could be administered to the patient.
Since we did not think about the next steps beyond the lab work yet, we did not know where to start. There are many aspects to consider when developing a cell therapy. For that reason, we found it difficult to determine what stakeholders we should contact. However, we understood that the outlook and implementation are essential parts of the project since all steps of drug development can have an impact on the design of our cell therapy !MPACT.
To get an overview of the aspects of the implementation we made a list of which stakeholders we should contact. As advised by Organon, cell therapy manufacturers were added to this list. Furthermore, we added stakeholders to this list that are experts in fields ranging from business plan development to regulations and safety regarding ATMPs, and cell therapy administration. Drafting this list helped us to get an overview of parties that should be considered to develop our cell therapy in the future. Furthermore, with literature we investigated the treatment procedure for cell therapies.
To clearly show the treatment procedure of !MPACT we created a cell therapy cycle (proposed implementation). In addition, we concluded that engaging stakeholders relevant to implementation of our project should have a high priority.
We plan to systematically engage with stakeholders from each phase of the drug development process that is necessary for successful implementation of !MPACT. These phases include R&D, production, administration, clinical studies, market authorization, and market access.
In order to perform our iGEM project in a good, responsible, and safe manner, we must comply according to the ethical regulations of our institution and the government. Because we collect sensitive data from people (patients) in interviews, we need formal approval for Human Subjects Research from our institution and we need consent procedures for participants.
Since we wanted to perform our project safely, responsibly, and according to iGEM’s values, we felt the need to handle the obtained data in a responsible manner. However, we did not know how we should do this.
We engaged with the Ethical Review Board and with a data steward at the Eindhoven University of Technology to learn how we should handle gathered data in a responsible and safe manner. Discussing our research project with these experts helped us to get insights into collecting, processing, and storing data in a responsible manner.
In order to act in a responsible way, we did three things. First, we made two informed consent forms: one for patients and one for other stakeholders. These informed consent forms were checked and approved by the Ethical Review Board. Secondly, we switched to a new server that is better protected and supported by our institution. Lastly, we filed a privacy impact assessment (PIA) for safe data collection, processing and storage that is approved by our institution as well. We now have official approval for all our Human Practices work.
We will send all stakeholders and patients an informed consent form before having a meeting. For the people we have already interviewed, we will still send them the informed consent form as soon as possible. Besides, we will transfer all our documents to the new server and remove redundant data. For personal data, we will anonymize the data as soon as possible and only keep the relevant information. Moreover, when discussing our project with patients we will emphasize that our project is a research project, and the therapy will not be on the market soon.
After meetings with pharmaceutical companies such as Novartis, ThermoFisher, and Organon we created business plan for !MPACT. We determined already that we would license our proof of concept of !MPACT to larger pharmaceutical companies as a revenue stream. We were encouraged by our partners such as Novartis to further work out this revenue plan. The challenge we faced was to determine how much clinical evidence is required to successfully license the IP of the proof of concept of !MPACT. Moreover, we had to make a calculated estimation of the required costs to work out and clinically test the proof of concept of !MPACT and a calculated estimation of the revenue we make by licensing it.
We experienced the task as quite difficult since our team has very little experience in starting a new business. Since we are at the initial phase of our new venture, it is difficult to make reasonable assumptions and estimations. Moreover, the required information for building a business plan around cell therapy is not explicitly available in the literature and thus requires many conversations with experts.
To work out our revenue plan successfully we tried to involve two different types of stakeholders. On the one hand, we discussed our business plan with large pharmaceutical companies such as Novartis to determine which clinical evidence is required to license our IP and what the associated costs of these clinical trials are. Secondly, we tried to involve small Med Tech start-ups that also produce cell therapies such as CiMaas. They could help us with shaping a successful business strategy and they could give insight into the costs a start-up faces. From this, we learned it is crucial to engage with different types of experts which allows facing a problem from multiple perspectives. We experienced that this gives the richest amount of information.
Based on discussions with the experts we learned that clinical evidence is required to license the proof of concept of !MPACT. We found out the best option would be that iGEM TU-Eindhoven performs clinical studies up to phase IIa. Larger clinical studies require many more resources that we don't possess and would be very expensive to acquire. Moreover, clinical phase IIa serves as the golden standard for sufficient evidence to license a proof of concept for a new therapy to a large pharmaceutical company. We also learned about the assumptions we could make to determine the costs of working out our proof of concept and the price we could ask for licensing our therapy. These details can be found in our on the Entrepreneurship page.
Now that we know the best business strategy to market !MPACT and since we now know the right assumptions to calculate the costs and revenues, we can complete our business plan for !MPACT. We will plan even more meetings with new venture experts to validate our business plan.
A challenge multiple stakeholders identified about our project is the controllability of interleukin 10 (IL-10) production. The University Medical Centers (UMCs) stressed that the immune system is very tightly regulated and a small difference in IL-10 concentration could lead to large consequences for the immune system. In addition, multiple stakeholders such as the RIVM and the BioSafety Officer of our university explained that the risks of a GMO to the environment and humans could be minimized if you have a way to kill or inhibit the GMOs by an external stimulus.
We were feeling hopeful to overcome this challenge because more iGEM teams faced the same challenge. Moreover, we are working on a predictive model, which we could use to predict and tune the IL-10 production based on certain input variables.
We evaluated the information we received in three ways. At first, we discussed with other iGEM teams during the Dutch meet-up for iGEM teams (communication), such as Wageningen UR 2022, the possibilities for a kill switch. Secondly, we discussed with experts such as the RIVM and UMCs the ways we could control the IL-10 production of our engineered cells. Lastly, we performed a literature study to find out the best way IL-10 production could be controlled. By approaching the problem from different perspectives, we could compare multiple possibilities and choose the solution that best fitted our design.
We decided to tackle the challenge in two ways. First, we want to use the model to predict IL-10 production. The model can subsequently be used to predict certain parameters such as the ideal binding affinity between ANCAs and the GEMS for sufficient IL-10 production . This parameter can, for example, be engineered in the lab to get the optimal IL-10 production. On the other hand, we decided we should consider a way to inhibit our engineered cells by external stimuli.
We made several predictions using the model, as can be found on the “Model” page and we worked out a way to inhibit the production of IL-10 by our engineered cells by making use of external stimuli. Details of this inhibition can be found on the “Proposed implementation” page.
For the outlook of our project !MPACT, immune cells from ANCA-associated vasculitis (AAV) patients will be modified to become engineered cells able to excrete interleukin 10 (IL-10) as the response of binding antineutrophil cytoplasmic antibodies (ANCAs). To decide which cells are to be collected and modified, either B- or T-cells, we have spoken to dr. Wilfred Germeraad from CiMaas and Prof. Reno Debets from Erasmus UMC. Both are active in the field of immunology. Whereas dr. Wilfred Germeraad suggested focusing on B-cells, Prof. Reno Debets proposed focusing on T-cells. After these interviews, we learned that both immune cells could suit our design but would meet different requirements of our project. Consequently, our team should determine which values and requirements must be prioritized and which compromises must be made to decide which immune cells we want to implement in our therapy.
We experienced the task of choosing between B- or T-cells quite difficult. Wilfred Germeraad and Prof. Reno Debets both mentioned valuable arguments concerning the immune cells suggested. Since both cells met some of our set requirements, we found it hard to decide which cell would suit our project best.
To make an informed choice, we decided to perform an extra literature study with a few team members to verify the arguments that had been given during the interviews. Moreover, we aimed to find new arguments that would enlighten which immune cell would fit our concept best. Subsequently, the findings were presented to the complete team to discuss whether B- or T- cells should fit our project vision best.
As a result of the discussion with our team, we decided that we cannot make a well-considered choice for now. Both B- or T-cells would fit our project vision, but by meeting different requirements. We suggest first investigating the possibility of T-cells since they are used in many cell therapies already and a lot of research into their mechanism of action is performed already.
The findings of this literature study will be elaborated on for the proposed implementation page.
Since our cell-therapy aims to regulate the immune system, it is important to consider the dual use of our new technology. The challenge was to figure out the dangers and dual-use potential of both synthetic biology in general, and our project in specific. Moreover, we wanted to know how dual-use of our project could be prevented. Together with iGEM Team BOKU Vienna (Partnership), we considered the potential dual-use of synthetic biology.
We were expecting synthetic biology could be misused, for example, as a bioweapon but at first, we did not really consider that also our project could be used as such.
To tackle the above-mentioned challenge, we engaged with some experts in the field, including Dr. Koos van der Bruggen and Dr. Mauritz Kelchtermans regarding bioweapons and biosecurity. They showed us previous examples of bioweapons that make use of synthetic biology. They elaborated in what way our project could be misused. Lastly, they shared some notes on how we could minimize the risk of misuse.
Although not very likely, it can be concluded that our project could be used for malicious reasons. Our project could, for example, be used as a bioweapon for personal attacks. However, it is not likely to be used in war, due to its non-specificity, complexity, and uncontrollability.
We implemented several measures to minimize the chance our projects get misused. These can be found in the meeting with dr. Koos van der Bruggen and the Proposed implementation.
At the beginning of our project, we had a clear view on the proof of concept of the therapy. However, the necessary steps between the proof of concept of the therapy and the therapy getting on the market, were not yet clearly defined.
We were eager to understand all aspects of the development of cell therapies. In our opinion, it was of great importance to understand the complete development process because it will help to create and design a better, more desirable product. Therefore, we felt the need to reach out to many stakeholders to learn about the future steps in the pipeline for the therapy !MPACT.
We received a lot of information from the stakeholder meetings with Koosje van Lessen Kloeke, CHDR, Johnson & Johnson, EMA, doctors and Zorginstituut Nederland (National Healthcare Institute). Each meeting was focused on another part of the development process of our cell therapy. We summarized all received information and created a clear overview of the complete development process of a cell therapy.
The complete drug development process for !MPACT can be found on the Proposed implementation page.
This overview of all necessary steps after the proof of concept is developed, is necessary to make a viable business plan, which can be found on the Entrepreneurship page.
With many stakeholders, we discussed the ethical discussions concerning synthetic biology. For example, we discussed with dr. Koos van der Bruggen the dual-use of synthetic biology and bioweapons. In addition, we discussed the dual-use and current ethical discussions about synthetic biology with dr. Mauritz Kelchtermans we discussed risk assessment for new GMOs in the environment with Greenpeace. However, we were also curious about the knowledge of the general public on synthetic biology. We wanted to know how they associated synthetic biology, how they gained their knowledge about it, what risks they see in synthetic biology, and what their opinion is on the use of synthetic biology (synbio) to solve global crises. Therefore, the challenge is to determine what the general public thinks about synthetic biology to find out how we and future iGEM teams should communicate with them.
The main feeling dominating was curiosity. For us, it was very difficult to estimate what the general public thinks and knows about it. We however expected education and age to influence people’s opinions and knowledge of synthetic biology.
To overcome the above-mentioned challenge, we decided to team up with iGEM BOKU Vienna. Together we surveyed the general public to gauge their knowledge of synthetic biology. More information about this survey for the general public with iGEM BOKU Vienna can be found on the “Partnership” page. Reflecting upon this partnership, we believe surveying with two teams is beneficial as you reach a larger and more diverse public. Moreover, it helped to discuss the results in more depth, and we could combine our team's strengths such as statistical analysis, creating surveys, data protection, etc.
When we designed our survey, we expected education and age to influence people’s opinions and knowledge on synbio. While education correlated with a better self-assessment of one’s knowledge about synbio, age is a contributor to more negative opinions on the potential and impact of synbio projects.
This draws focus to an often-neglected perspective - the importance of education at any age. Education about synbio is not something to be covered by educating the coming generations. Educational efforts to the general public should include concepts and projects focussed on adults and the elderly who may have struggled to keep up with the quick changes on the scientific horizon. An informed, scientifically literate public is more important than ever, and it is on scientists, young and old, to spread scientific communication to communities beyond their profession.
We sincerely hope that these results further demonstrate the need for future iGEM teams to work on outreach material targeted at older generations as well as communities often left out of scientific discourse due to occupational differences. In future work, it would be amazing to see similar analyses focused on underrepresented communities.
To determine whether our project is good and responsible for the world, a lot of effort was put into involving as many stakeholders as possible during the entire journey of our project. We involved nearly 30 relevant stakeholders from different communities including industry, academia, healthcare, patients, government, public organizations, and local communities. With experts in different fields, we discussed the science underlying our project, the societal need for our project, its proposed implementation, our business idea, ethical and safety aspects, and the current laws and regulations that are in play. We engaged with all stakeholders to understand their values and needs, which we integrated into our own values and translated into tangible design requirements for our project !MPACT.
We felt ambitious in trying to engage numerous stakeholders in our project. At the start, we were afraid that many stakeholders we identified as relevant would not want to participate in our project.
To systematically approach relevant stakeholders, we created an HP team consisting of 5 team members. We started with an extensive brainstorming session in which we identified relevant stakeholders for our project. We made a structured plan containing all stakeholders we would approach. We implemented a timetable that guided us with when to approach which stakeholder. We closed the feedback loop by validating the integrated feedback with different stakeholders in the same field, with literature, and with recurring meetings with the same stakeholder.
We made sure all Human Practices work was clearly documented on the Human Practices wiki page. This page eventually links all efforts by making use of clear frameworks such as the stakeholder identification map, value-sensitive analysis, an extensive timeline that makes use of AREA frameworks (framework to modify research and innovation in response to societal issues), and Gibbs reflection cycles to reflect upon decision-making based on the feedback we received. The frameworks build upon previous iGEM work and serve as an inspiration for future iGEM teams to build upon even further. The founding of a separate HP team, a strict division of tasks, clear documentation, and well-structured planning allowed for efficiently approaching all stakeholders required and integrating their feedback, values, and needs in our project in the best way possible.
The Human Practices work had essential consequences for the core and direction of our project from the start. Feedback from the stakeholders determined the goal of the project and its application. Furthermore, the feedback was implemented in lab experiment designs, model objectives, education purposes, the proposed implementation, partnership objectives, the entrepreneurship plan, and how we operated and communicated as a team. We managed to include all relevant stakeholders to prove our project is good and responsible for the world.
We sincerely hope that our method for integrated Human Practices inspires future iGEM teams to use similar approaches, including frameworks, analyses, brainstorming sessions, and wiki visualizations we use. In future Human Practices work, it would be amazing if similar methods would be used to investigate if a project is good and responsible for the world.
To close the loop between what is designed and what is desired, we had multiple conversations with the same stakeholder to discuss whether we integrated their feedback in the right way. Moreover, we tried to involve multiple stakeholders from the same field to create a broader opinion on our project design and to validate the advice of single stakeholders. The combination of multiple meetings with similar experts and literature studies enabled us to critically reflect on our design at each moment of the design process.
Secondly, we tried to close the loop between what is designed and what is desired by proposing the implementation of !MPACT (Proposed implementation). In this section, you can read each step that is necessary to bring !MPACT into the real world and what design of !MPACT is eventually required. With the help of our human practices work, we propose how our design should be further improved and what actions we as a team should take to successfully introduce !MPACT to the market.