Integrated Human Practices

Vision and mission

The goal of the human practices team has been to bring IBD NanoBiotics out to the world and shape its realisation by integrating the collected knowledge and experiences to adapt our project to the needs of the targeted interest groups. Our vision for implementing our human practice outreach strategy is to guarantee the development of a suited treatment option. We referred to the word suited as an encapsulation of our mission to:

• Involve IBD researchers and medical professionals and collaborate together on the design of an effective and specific therapy and grasp the current clinical picture
• Understand the patient’s problems and implement an innovative solution towards their mitigation
• Involve the general public to increase the acceptance of our innovative therapy by making our research accessible and understandable
• Educate the future generation on key biological concepts needed to understand our issue and familiarise them with scientific thinking

Identifying and addressing the different interest groups for the development of IBD Nanobiotics

At the early stages of our project, it was clear that our endeavours to come up with a new targeted treatment option could only be successful if we brought our project into the world. We were interested in involving people touched directly and indirectly by our issue of focus already in these early developmental stages. The idea was to integrate the inputs and experiences of these groups to fulfil our vision to come up with a suitable treatment option for IBD. We collaborated with IBD researchers, gastroenterologists, business developers, stakeholders and federal regulatory authorities on different areas of the project development. Further, we aimed to work closely associated with IBD patients to develop a therapy for and with them. Lastly, engagement with the general public was essential to address the acceptance and understanding of our issue of focus: developing a specific and targeted treatment option for IBD.

Shaping of IBD NanoBiotics through expert hands

Once we fixed our project idea, the outreach to different experts was crucial to help us set the direction of research and implementation. For instance, the outreach to IBD researchers and gastroenterologists was essential to develop the right therapy approach and choosing the target molecule for our nanobodies. We decided to target tumour necrosis factor (TNF) as advised by Prof. Dr. med. Dr. Phil. Gerhard Rogler, a gastroenterologist and experienced researcher on IBD. TNF is a general marker for inflammation and is not specific to certain areas of the gastrointestinal tract making the application of IBDNanoBiotics possible for both Crohn's Disease and Ulcerative Colitis. However, previously we had to understand how to work with nanobodies and scale it down to our available time frame. For this, Prof. Dr Markus Seeger and members of his lab were a great help in defining our project's framework and answering our questions. Here, we understood that we needed a soluble target to work with nanobodies. Therefore, our previous idea to target pH sensing receptors based on literature research was not feasible because purifying these receptors would be a difficult challenge to overcome. Moreover, to successfully bring our project outside the laboratory, it was necessary to connect with experts to help us understand what a translation to a clinical application would look like. Therefore, we have worked with the regulatory offices concerned with the market approval of our solution to understand their requirements to apply for a permit to conduct clinical trials with GMOs. For Switzerland, this is a novel area of research in which, at the moment, there is no approved GMO-based therapy. Finally, hand in hand with the application for market approval comes the development of a business plan to secure the resources needed to develop our project.

Inclusive therapy research: a special foucs on IBD patients

The main aim of our iGEM project is to lay the foundations for a novel targeted treatment option using a synthetic biology inspired approach to tackle the limitations of the current standard of care and understand how our project can ameliorate the quality of life of IBD patients. Therefore, including IBD patients with their experiences and needs was particularly important for the human practices team. Hence, to understand the patients' problems and implement our innovative solution towards their mitigation, we partnered up with the patient organisation Crohn Colitis Switzerland (CCS), the biggest patient organisation for people living with IBD active in all four Swiss language regions. CCS engages in building a national network among IBD patients and acts as an information and exchange platform. We had the opportunity to talk to the organisation’s president and introduce our iGEM project, particularly focusing on our aim to conduct patient-centred research. We were very fortunate to get their support which led us to the establishment of the core piece of our patient integrative approach: the IBDNanoBiotics cohort study (IBDNCS).

A cohort study on IBD in Swiss patients: clinical picture analysis and status of IBD NanoBiotics among Crohn's disease and Ulcerative Colitis patients

Aim of the cohort study

The main goal of our iGEM project was to lay the foundations for a novel targeted treatment option for IBD. However, to understand the different layers of our problem and include the broad clinical spectrum of IBD, we decided to recruit patients via CrohnColitis Schweiz and establish the IBD Nanobiotics Cohort Study with the aim to:

• assess the occurrence of Crohn’s disease (CD) and Ulcerative colitis (UC) in a subset of IBD patients in Switzerland
• understand the impact of IBD on their body and daily life
• get a picture of the current standard of care with its efficacy and side effects
• advance and tailor IBD NanoBiotics to cover patients’ needs.

Key findings

• IBD is a disease that affects all age groups
• IBD does not only cause symptoms in the gastrointestinal tract and patients often suffer from comorbitites
• TNF inhibitors are the most used therapy among IBDNC participants
• The need for a treatment that induces remission and maintains a symptoms free state is crucial
• 25 in 615 patients do not benefit from any therapeutic option available

Methods

The data was acquired through an anonymized questionnaire developed by the human practices team. The questionnaire was available to patients electronically in English, German, Italian and French; the latter three being official national languages. The questions were designed with the aim to allow the patients to disclose the amount of information they felt at ease with by allowing the selection of multiple pre-written choices and the free text option. The questionnaire was approved by the responsible ethics committee member for the faculty of Science of the University of Zurich.

Demographics

The questionnaires in German, Italian, French and English were filled out by a total of 615 patients, whereas the majority answered the questionnaire in German. The gender distribution is shown in figure 4 with the absolute number being 412 and 203 for females and males respectively. The results point out that there might be a gender-specific difference in the prevalence of IBD. A comparison with the literature revealed (1) that higher rates of CD are observed in females in the EU and US whereas in Asia the opposite (higher rates of CD in males) is the case. However, age seems to play an additional role in the risk of developing UC or CD in female and male subjects, so further research on the gender epidemiology of IBD is necessary to confirm a valid trend.

Surprisingly, the distribution of the two main conditions, Crohn’s disease and Ulcerative Colitis, usually summarized by the umbrella term IBD, were almost equally represented in the IBDNCS, as summarized in table 1.

The age distribution of the patients ranges from the youngest participant being 5 years old to the oldest participant being 90 years old. The age distribution of the IBDNCS is displayed in figure 5. Therefore, our data show that people from all age groups can suffer from IBD. Research on the prevalence of IBD in the Swiss population shows an increasing trend in all age groups (2), underlying the urgency of research on the exact etiology and successful disease management to dampen the costs on the health care system.

Current clinical picture

Symptoms

A significant point of interest for our team was to understand the clinical manifestations of IBD and zoom out of the molecular details we were really engaged with during our research on the design of IBD NanoBiotics. The spectrum of the symptoms we were able to register is shown in figure 6.

Diarrhea, abdominal pain, fatigue, bloody stools and unintended weight loss were the most common symptoms among the patients of the IBDNCS. Our data matches the symptoms described in the literature closely (3). Further, this data reveals that IBD is a condition that not only impairs the function of the gastrointestinal tract but has detrimental effects on the function of other organs. In addition, 80 % of the patients suffer from fatigue confirming the literature research findings. Therefore, we were interested in understanding if and how this and other symptoms would impact the daily life of IBD patients.

The answers were classified into representative categories as shown in figure 7.Sadly, only about 20 % of the patient cohort reported no or little adverse effects on their daily life because of their disease. These detrimental effects showed us the urgent need to come up with a therapy that decreases gastrointestinal symptoms. Hence, it is of utmost priority to avoid feeding into the vicious circle that patients often told us about: inability to leave the house because of constant diarrhea reinforces the feeling of helplessness and loneliness that further decreases their quality of life.

Standard of care – current pharmacological interventions

Today, the exact etiology of IBD remains still a mystery to solve. Research has suggested a multifactorial mechanism where genetic and environmental factors seem to be playing an important role (4). Therefore, current pharmacotherapies focus on reducing the symptoms to enable remission and normal daily life. To develop our own solution, the engineering of a probiotic bacterial chassis, we needed to understand with which therapies patients are being treated and to what extent their application is successful at managing their symptoms. Previous research (5, 6) on the European Crohn’s and Colitis Organisation ECCO guidelines for treatment of UC and CD helped us to categorize the data in their respective categories.The results are summarized in figure 8. Most of the IBDNC study participants are currently treated with tumor necrosis factor alpha (TNFα) inhibitors consisting of intravenous infusions of monoclonal antibodies against this key proinflammatory cytokine. Interestingly, 6% of the IBDNC patients are at the moment on no treatment. An overview of the most used therapies in the IBDNC, their mode of action (7)(8) and approximate price in Switzerland for a category representative is given in table 2.

Further analysis of the cohort data revealed that 214 (34.5%) patients do not suffer from side effects caused by the current treatment. On the other hand, the rest of the patients indicated suffering from side effects due to the pharmacological intervention. The range of indicated side effects varied vastly across the cohort sample. The results are displayed in figure 9. Notably, the majority of the side effects are not stemming from the therapy but are a remnant of the symptoms caused by IBD,which cannot be completely alleviated. This finding suggests that the need for a treatment that induces remission and maintains a symptoms free state is crucial. Moreover, inquiries about the clinical history of the patients were conducted to understand the tolerability and effectiveness of the therapeutics available. The results are summarized in figure 9.The findings obtained from the data analysis shocked us: 39% of patients indicated to have tried from 3 to up to 10 different pharmaceuticals.

Unfortunately, for 4 % of the patients (25 in 615), no available treatment option shows any success. Collectively, these findings highlight the urgent need for an efficacious therapy!

Finally, we used this cohort study to understand how much patients knew about the science behind our novel idea for a targeted treatment option. Results showed us that merely 30 % of participants had ever heard of synthetic biology. We further refined the analysis to assess if the knowledge about GMOs, the primary mode of action for our therapy, would be more widespread among our participants. We found that a significant proportion of the participants had not heard about GMOs. Therefore, the human practices team tackled the absence or scarce presence of information on GMOs and synthetic biology by implementing and designing two important tools:

Patient laboratory workshops: an occasion to become a scientist for a day

To give patients the opportunity to apply the concepts and techniques that have accompanied our wet lab team on the journey to equip our chassis E. coli Nissle 1917 with the needed genetic circuits, we carried out on two Saturdays in September 2022 our patients' dedicated laboratory workshops. Participants were recruited with the help of CCS. The workshops took place at the teaching labs of the Biochemistry Institute of the University of Zurich. After a brief introduction and presentation about our project and synthetic biology, it was time to wear lab coats, gloves and goggles, head to the lab and beginn pipetting!

In between incubation and waiting times, we offered a small buffet with IBD friendly baked goods and drinks for our participants. These workshops were a place of great exchange between us and the patients. We noticed how much they valued being involved in our project. We were very excited in noticing that the patients had a great interest in understanding and applying science and were thrilled to answer questions like “How come that the plasmid I am isolating is not degraded when I open up the bacteria?”. Overall, we were very happy with the results of the workshops and received wonderful feedback from the participants. The success of these interactions motivated us even more to keep working with passion and endurance on IBD NanoBiotics.

Understanding IBD on an individual level: an interview with Marcel Brunner

The patient workshops showed our human practices team how important interactions on a personal level are for connecting our project with patients. Also, these interactions helped us practise our science communication skills and break down key project questions to a simpler level. Hence, we contacted Marcel Brunner, an IBD patient who is committed to spreading awareness on IBD and breaking the taboo of intransparent communication about the limitations and difficulties patients face on a daily basis. Below a section of the interview Martina and Len conducted together with Marcel.

A project for everyone: getting IBD NanoBiotics to the community

Pioneering a research field always comes with many questions and fears that need to be discussed. Our primary goal in the outreach and education field was to initiate the dialogue in the community about the revolutionary approach we are proposing to implement in order to increase its acceptance, identify criticism and support our idea with accurate information- just like we would in the lab. Therefore, it was crucial not to limit our outreach to patients and medical professionals and involve the general public. Hence, for the general public, we set ourselves two goals that we aimed to fullfill:

• increase awareness about IBD and the lack of an effective treatment option
• introduce the concept of using synthetic biology for biomedical research
• focusing on introducing GMOs as a novel drug delivery option

To introduce the concept of GMOs as live therapeutics, it is fundamental to first acquaint society with the biology and functions of bacteria that we aim to profit from. Therefore, we started our educational efforts with young primary school students and designed a workshop dedicated to the importance of bacteria and gut microbiota for our health. Further, we continued with high school students' workshops at the life science learning center (LSLC) of the University of Zurich. The LSLC is an educational center for school classes of all ages that offers laboratory workshops ranging from microbiology to genetics to neurobiology. Our workshops focused on delivering the main concepts about the characteristics of GMOs on an accessible level coupled with hands-on laboratory work. Further, we gave insight into synthetic biology, and examples of the many applications scientists have thought of. Training the scientific thinking skills of the next generation of researchers was the strength of the high school lessons we had the opportunity to teach. Finally, to tackle ethical and philosophical questions that applying synthetic biology poses, we teamed up with Reatch. This organization focuses on the establishment of a science-friendly community. Under this framework, Reatch organizes discussion rounds to combine science and philosophy and enable their discussion. Hence, we organized a discussion evening for university students with different backgrounds on synthetic biology in medicine. This exchange was essential to show us what ethical problems we could face with our project and the general advancement of synthetic biology in medicine. To reach an even broader public, we used our social media accounts to increase awareness about IBD, for instance on World IBD day.

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