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.

Patient Involvement

Engaging with patients - the end-users of our product - was important for understanding the unmet patient needs that we are aiming to rectify. Our initial engagement with patients was in the form of surveys that were distributed to patient groups for a variety of autoimmune diseases. The results of the survey were useful at providing an overview of the common issues faced by patients and the common side effects of existing medication. 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.

Safety

Regulation

Before we could proceed to analyse the business model environment, we need to look at the laws and regulations surrounding our therapeutic. Without going through these, we would not be able to reach the business model stage. Therefore on the business side, the priority is to go through the clinical trials which can take 10+ years, after getting a patent. These can be costly: phase 2 clinical trials cost $15,800,000 and in phase 3 cost $14,500,000 for gastrointestinal diseases.

Regulation Flowchart

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.

People We Worked With

As well as the students, public and patients we worked with throughout the project, we are incredibly grateful for the support and advice we gained from a wide range of professionals.

Dr Tony Cutler - Wellcome Trust Centre for Human Genetics

As an immunologist specialising in Type 1 diabetes and autoimmune diseases, Dr Cutler 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 to understand whether the production of IL-10 may have beneficial anti-inflammatory effects in individuals suffering from autoimmune diseases. He highlighted the importance of safety, and encouraged us to speak to patients and clinicians to understand how a GM probiotic may be accepted in clinical settings.

Professor Simon Travis FRCP - Professor of Clinical Gastroenterology

Professor Travis provided us with valuable advice based on his insight as a practising clinician. He believed that a GM probiotic would be a safe treatment, although he advised us to consider the possible complications of the treatment escaping into the environment when excreted by patients in areas with poor sewage systems. In light of this, we designed a kill switch to ensure that our bacteria will not function when outside of the human gut. Professor Travis also advised us to focus our efforts on the treatment of autoimmune diseases of the gut, as opposed to autoimmune diseases in general, based on the heterogeneous nature of different autoimmune diseases. He also recommended that we consider the strain of bacteria we would use in the final therapeutic product since it is vital that the bacteria adhere to the wall of the gut. He provided us with information on clinical trials using IL-10 to treat Crohn’s disease and recommended the use of IL-10 therapy as opposed to other anti-inflammatory molecules (such as anti-TNFa).

Dr Hannah Chen - Translational Gastroenterology Unit, University of Oxford

Dr Chen gave us further 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.

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 the design of our probiotic. 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 encouraged us to research the evidence from clinical trials using Dekavil - IL-10 conjugated to an antibody - to treat arthritis, and to consider whether similar conjugation methods could be used in our product to prevent protease breakdown within the gut lumen.

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.

Dr Nick Thomson - Quadrum Institute, Norwich

Dr Thomson gave us an invaluable insight into the delivery mechanisms of probiotics and how to ensure the probiotic bacteria establish a niche within the microbiome. He gave us guidance on the types of strain to use in the probiotic product, introducing us to studies demonstrating that VSL#3 (a polybiotic solution containing many different probiotic bacterial strains) can be taken orally to improve Crohn’s disease. This gave us a useful direction for our research into probiotic strains and probiotic delivery. He also gave us useful ideas for areas of further research to test our product, such as using a model colon - with varying concentrations of oxygen and carbon, to test the bacteria in environments similar to the natural colon. He also praised our kill switch designs, again highlighting the importance of addressing the safety concerns associated with GM probioitcs.

Dr Chris Barnes - Department of Cell and Environmental Biology, UCL

Dr Barnes provided useful information about the colonisation of probiotic bacteria in the gut, demonstrating the importance of choosing the right chassis. He also suggested that we should focus on controlling the bacterial population size and should consider quorum sensing as a method of ensuring that the population remains at a constant level.

Dr Sam Parsons - Oxford Centre for Emotions and Affective Neuroscience

Dr Parsons is a psychologist and he shared information about the psychological impact of autoimmune conditions, including the psychological impact of chronic pain, isolation, stigma, and phobias of hospitals/needles. This enabled us to understand further complications of autoimmune diseases, and encouraged us to choose an oral form of probiotic delivery in order to create a minimally invasive, easily administered treatment.

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.

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 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.

References