Overview

An important aspect of synthetic biology is the consideration of how the technology has applications in the context of the wider society. We believed that collaborating with scientists, clinicians, social scientists, patients and the general public was essential to ensuring that our product benefits society. Our approach to human practices involved working with professionals, patients and the public to understand their opinions about various aspects of our project, and using this feedback to alter the design of our project and tailor our educational outreach activities.

The focus of our work on human practices was to integrate four major themes:

- Applied Design

Our approach to applied design involved creating surveys and interviewing patients to analyse the unmet patient needs and the most important issues that require addressing to improve patients’ quality of life. Regular conversations with patients, as well as professionals with knowledge in the law, manufacture and clinical delivery of therapeutics, enabled our design to continually evolve in light of this feedback.

- Public Engagement and Outreach

As a field still in its infancy, public knowledge of synthetic biology is limited and is often viewed with scepticism. As a result, public acceptance of genetically engineered therapeutics will be restricted by public knowledge unless educational resources are provided. The provision of summer school classes, public outreach events, online resources and a long-term public education plan were parts of our public outreach efforts. Our public engagement was integrated with our work covering applied design, as we remained open to feedback and used guidance from the public to shape our product design.

- Entrepreneurship

Our focus on entrepreneurship was a way of understanding how our therapeutic could be transitioned from the lab into the real world. We interviewed IBD patients and other key decision makers to determine the best value proposition. We surveyed the public about their preferences for potential products, and considered patents and regulatory procedures governing how our therapeutic can be taken into market.

- Safety

Safety is an essential consideration for the design of any genetically modified organism, particularly those used as medications. Discussions with clinicians and researchers, as well as some of the questions raised by patients and public we spoke to, encouraged us to make safety a key focus of our integrated human practices. Taking on the advice of professionals, we developed different designs of a kill switch and modeled the safety risks associated with our design.

Detailed information about our work centred around each of the four themes can be found on the respective pages of our wiki.

First Survey

When we were first coming up with a project we involved the public by reaching out from our social media with a survey. We assessed the general awareness of genetic engineering and asked which real-world issue they believed should be the focus of our project.

The overwhelming majority of survey participants picked therapeutics as an area of priority, this influenced the development of our project into a therapeutic based idea from our initial ideas.

Patient Consultation

After deciding on which issue we should work on we came across autoimmune diseases and believed current treatments are not sufficient. To ensure this was the case we consulted patients and clinicians and asked specific problems that result from the disease and current treatments

Patient Interviews

Engaging with patients - the end-users of our product - was important for understanding the unmet patient needs that we are aiming to rectify. This gave us an insight into what features will be important in the design of the product, although it became apparent that it would be beneficial to conduct one-to-one patient interviews to gain a greater understanding of the specific impact of the disease on patients’ quality of life. Taking on advice from clinicians, as well as the apparent range of symptoms associated with different autoimmune diseases, we chose to focus our product on the treatment of IBD. As a widely accepted method of “gaining insight into people’s feelings, understanding and perceptions”, one-to-one interviews played an important role in understanding the issues that our product must rectify to have the most significant benefit to patients’ quality of life.

We have gone into more depth on the conduction and results of patient interviews in our product design section. The results clearly show current treatments are not sufficient. The main points we took away from the interviews are that patients seek treatments that reduce flare-ups, have fewer long term side effects and less of an impact on social life. This greatly aided in the development of our device.

Autoimmune Disease Survey

We sent out a survey for patients with autoimmune diseases in order get a better idea of what patients would like from a treatment. We received 48 responses from members of the public suffering from autoimmune diseases from a range of age groups. The responses gave us a greater understanding of the current treatments, the problems with them and what patients would like from a treatment. We were astounded by the positivity towards GE and for our project. There is a great deal of belief from the public in the potential of GE in medicine.

They survey told us the public wanted a treatment that treats “a condition at its source rather than masking symptoms.” that was also “less invasive and less dangerous”. They also showed support of a device that was able to provide personalised doses according to the patient. This led to the initial design of our treatment.

Developing our design

Having received feedback from patients we learnt what was sought after in a novel treatment. We then reached out to specialists to comment on the initial design of our device in order to maximise the efficacy of our treatment based on current knowledge on the immune system and IBD.

Dr Hannah Chen - Translational Gastroenterology Unit, University of Oxford

Dr Chen gave us guidance about the treatment of Crohn’s disease and other inflammatory diseases of the gut, highlighting the fact that the symptoms and cause of Crohn’s disease are heterogeneous. Her insight made us consider the range of inflammatory markers that vary in individuals with Crohn’s disease, prompting us to undertake further research into biomarkers for Crohn’s disease. Dr Chen recommended reading about certain research studies, and this enabled us to find evidence to demonstrate that luminal NO is a suitable biomarker for Crohn’s disease, as well as providing quantitative data for use in modelling. Dr Chen also discussed the importance of the microbiome and the general lack of understanding among the public, which encouraged us to create an information leaflet about probiotics and the microbiome, you can find this in the public engagement section.

Dr Tony Cutler - Wellcome Trust Centre for Human Genetics

We met with Dr Cutler, an immunologist specialising in Type 1 diabetes and autoimmune diseases, to gain knowledge of how autoimmune conditions occur. He provided us with an invaluable insight into the pathogenesis of autoimmune diseases and how anti-inflammatory molecules may have the potential to have therapeutic effects. We met with him during the early stages of the project, he encouraged the use of IL-10 as it has beneficial anti-inflammatory effects in individuals suffering from autoimmune diseases. He highlighted the importance of safety, and encouraged research how a GM probiotic may be accepted in clinical settings.

Professor Chris O’Callaghan - Nuffield Department of Medicine

Professor O’Callaghan’s knowledge of biomarkers of inflammation and immune functioning provided us with important advice in the use of biomarkers in our design. He highlighted key studies involving biomarkers, such as evidence to show that exhaled NO is correlated to disease severity in asthmatics, to demonstrate the potential of developing an NO-based treatment method. He introduced us to the idea of altering the structure of IL-10, such as by conjugation to another molecule, to increase the transport of IL-10 to sites of inflammation. He led us to the research from clinical trials using Dekavil - IL-10 conjugated to an antibody - to treat arthritis, and encouraged us to consider whether similar conjugation methods could be used in our product to prevent protease breakdown within the gut lumen.

Andra Necula - Doctoral Training Centre, University of Oxford

Andra provided detailed guidance regarding the use of metabolic markers to approximate immune cell populations in the intestine. In addition to highlighting the suitability of adenosine as an indicator of Treg function, she was able to provide key concentration ranges that we were able to incorporate into our model. She also advised us on future experiments we could carry out in order to gather further data reflecting the efficacy of the system, both using immune cells in vitro, and in appropriate model organisms in vivo. You can read more about these in our future experiments pages.

Dr Chris Butler - Nuffield Department of Primary Care Health Sciences

Dr Butler’s experience in Primary Care provided us with an important understanding of patient’s perceptions and their likely responses to the use of a GM probiotic. Dr Butler believed that patients understand the concept of ‘good’ and ‘bad’ bacteria existing, but believed that the majority of patients would still be surprised, and probably sceptical, about the use of taking bacteria as a treatment. This reinforced the importance of educating the public about probiotics and the benefits of a diverse microbiome, therefore encouraging us to develop an educational leaflet about probiotics and include this subject as one of the key focuses in our Long-term Public Education Plan. Dr Butler is the Principal Investigator of the PRINCESS (Probiotics to reduce infections in care homes) Trial, so provided information about the effectiveness of probiotics. He provided information about the microbiome becoming less diverse with age, but informed us that there is currently no evidence to suggest that probiotics become less effective with age - this suggested that our therapeutic should still be functional in more elderly patients.

Professor David Greaves - Sir William Dunn School of Pathology, University of Oxford

Professor Greaves highlighted the importance of ensuring that the delivery of IL-10 is controlled, drawing upon evidence from his own experiments that demonstrated the health risks associated with excessively high expression of IL-10. He provided us with papers and further reading which allowed us to understand the range of healthy concentrations of IL-10 that we could use for modelling the adenine-induced negative feedback loop.

Professor Luzheng Xue - Nuffield Department of Medicine, University of Oxford

Professor Xue gave us useful advice on the molecular and cellular mechanisms involved in the pathogenesis of inflammatory diseases. He recommended that we should research the other sources of NO, such as endothelial cells, and to ensure that this is considered when modelling the system.

Safety

Regulation

Regulation Flowchart

Dr Michael Morrison - Centre for Health, Law and Emerging Technologies (HELEX)

Dr Morrison met with us on multiple occasions to discuss the law and regulations that would be relevant to the development of our product. He gave us guidance on the various regulations that would govern how our product could be used clinically, and gave us an understanding of the processes required during clinical trials. In light of our work with Dr Morrison, we created a proposal on the safety of GM probiotics, a long-term public education plan, and theoretical plans for completing clinical trials and the manufacture of our probiotic.

Cell and Gene Therapy Catapult

Catapult is a centre to help and encourage growth of cell and gene therapies by aiding with regulation, product testing, logistics, manufacture and business advice.

We met with Daniel Rabbie, the Regulatory Affairs Manager, and Ryan McCoy, the Senior Process Development Scientist to discuss how our product fits in with current government regulations and how we can take it from the lab to the patients. We discussed the differences in regulation in different therapies, the organisations available to speed up the process of getting the treatment from the lab to the patient, current therapies, and considerations involving logistics and manufacture.

ATMP Classification

Our treatment would likely count as an Advanced Therapy Medicinal Product (ATMP) according to the European Medical Agency (EMA). The classification of a therapy is particularly useful for clinical trial design but also helps for its specific regulation, its licensing and what advice is available. The EMA’s Committee for Advanced Therapies (CAT) advise on whether a treatment would be considered an ATMP and what type it would be, such as a cell or gene therapy. CAT has a list of previously categorised treatments. In this list we found a therapy involving modified Lactococcus Lactis engineered to produce anti-TNF alpha antibody fragment for the treatment of Ulcerative Colitis. This treatment is very similar to ours allowing us to use this as a basis of what our treatment would be classified as. Even though the patient’s genome is unaffected this treatment still counted as a gene therapy medicinal product as “The introduced recombinant sequence is directly related to the therapeutic effect”. To confirm our treatment has the same characterisation we have submitted an application for ATMP classification with CAT from the EMA which we are waiting to hear back from. Our completed form can be read below. The form can be confusing especially for those lacking knowledge of drug regulation, as we initially did. We are hoping this can be used as a reference for others seeking classification of new types of medicinal therapy in the EU.

References