Team:Oxford/Human Practices

Human Practices

Overview

Human practices has been a core focus of our project throughout its entirety. As a therapeutic focused project we have interacted with previous C. difficile infection (CDI) patients and at risk groups, who could be future patients, to identify their needs and provide better treatment options for them. This ensured that our project would cater to their needs and increase the quality of their care. Interviews with previous CDI patients have helped us to decide on our delivery method and validate our safety considerations. We also conducted interviews with over 65s, who are the most at-risk group in society for CDI, in order to discuss their safety concerns and provide them with information about genetic engineering and how we are using it. We talked through the risks and how we had dealt with them; to both refine our design and reassure future patients.

Within the technical aspects of the project, we have had an vast amount of input from professors and experts who are all leaders in their field. We have also been very lucky to talk to a multitude of industry leaders about our project, including CEOs of microbiome start-ups: Zack Abbott from ZBiotics and Soren Thomsen from BioMe. Take a look at our timeline to see how each interaction influenced our design up to where we are today.

Timeline

Advisors

Dr. George Wadhams

Professor - Oxford Department of Biochemistry

George Wadhams is a Professor in the Department of Biochemistry, specialising in bacterial signalling. We discussed in detail the potential signalling pathways that we could use to detect C. difficile bacteria. In the end, we decided that the best method would be to utilise C. difficile’s own signalling system to sensitively detect its quorum signalling molecules which signify an imminent release of toxins. According to our modelling, this decision also alleviated cellular stress, which would have otherwise limited production of our endolysin by the L. reuteri cells.

Dr. David Eyre

Robertson Fellow and Infectious Diseases Clinician- Oxford Big Data Institute

We then spoke to David Eyre who was instrumental in helping us to decide on our probiotic chassis. After the decision to implement a detection system, we came to him with a list of requirements for our probiotic, to enable its dual functions of C. difficile sensing and killing. Our chassis would have to be able to express the C. difficile two component signalling system in its outer membrane to enable detection of the quorum signalling molecule. It would also need to be able to secrete the endolysin and not be lysed by it. In order for it to be a probiotic treatment, the chassis would also need to be able to survive in the gut. L. reuteri fulfils these criteria by being a gram positive bacteria that is not affected by the endolysin’s lytic activity.
A further literature review demonstrated previous work that had used L. reuteri as a chassis as Staphylococcal aureus detection system, also using the quorum sensing molecules. This gave us confidence that we could do the same for C. difficile in L. reuteri.

Dr. Frances Butcher

Doctor of Public Health

Dr. Frances Butcher is an expert in bioethics and biosafety and gave us invaluable insight into a central part of the project. She influenced our project in both outreach and product design. Having worked as a fully qualified doctor in hospital wards, she was able to give us insight into drug prescription and administration processes for CDI. Furthermore, C. difficile was a considerable issue at her hospital and she explained some of the standard treatments and their limitations, such as antibiotic therapy and fecal microbiota transplants. It was very interesting to hear about CDI from the point of view of a doctor who had dealt with the infection first hand.

We also discussed the concept of kill switches, which are often thought of as a requirement for genetically engineered products. However, Dr. Butcher emphasised that the kill switch must have a scientific objective and “must not be used to solely treat societal anxieties.” In fact, including a kill switch might lead to a negative public perception as it invites people to question the safety and potential risks of our probiotic. As a result of this, we ultimately decided not to incorporate a killswitch into our ProQuorum bacteria and instead rely on the sensitivity of our detection system. She also encouraged us to concentrate our efforts on outreach and educational activities to counter fears and misconceptions about genetic engineering which could affect perceptions of our product.

Survey data

Therefore we conducted a public survey (together with iGEM Leiden and Copenhagen) about medical genetically modified organisms (GMOs) to find the out most common fears and misunderstandings surrounding them. This allowed us to specifically address these concerns in our outreach activities. Some of the most important results from our survey are highlighted here:

Survey Methods

Our methods for conducting the survey were approved by our supervisors as well as the institution. We designed our survey in compliance with the AAPOR Task Force report “Evaluating Survey Quality in Today’s Complex Environment” and Best Practices for Survey Research guidelines: The survey was anonymised and our methods for conducting the survey were approved by our PIs and the institution, respectively. We pretested questionnaires and procedures and afterwards we tallied all of the surveys to get our final results. The survey itself contained a disclaimer paragraph informing the participants about the purpose of the survey, and contact information for any concerns. This was followed by two demographics questions, and then five questions designed to better understand public understanding, reaction and opinion of GMOs. Finally, two questions were designed to give us specific opinions about the drug designs of our individual projects. In the end participants could give us any further comments on our projects or survey, as well as any concerns. We purposefully decided against a fully multiple choice survey to give participants the chance to give their differentiated and unbiased opinion. Finally, we performed a detailed analysis of the survey to get the final results.

Overall, 221 people filled out our survey. Because it was an online survey, and we sent it out through social media amongst others we were aware that our polling population might have some bias. We saw this bias in our demographic results, where the average age was 29.3 years old and 24% were within typical university student age. However, we still think that our data can provide some useful insights into the general population’s opinions. 102 of the participants were from the UK, 54 from the Netherlands, 31 from Denmark, and 35 from other countries. As our survey was online and we used social media to publicise it, we were aware that our polling population might have some bias. As expected, we saw this bias in our demographic results, where the average age was 29.3 years old and 24% were within typical university student age. From graph 1 it can be seen that the majority of the people that answered our survey were under 25 years old: 64,5% were under 25 years old, 16,8% were between 25-40 years old, 12,1% were between 41-65 years old and 6,5% were over 65 years old. However, we still think that our data can provide some useful insights into the general public’s opinion.

General Opinion on Genetic Engineering

Graph 1: The general opinions on genetic engineering by age groups

The aim of the survey was to understand the general opinion about genetically modified organisms. Our survey showed that most people are actually quite positive about genetic engineering. People over 65 years old are the most enthusiastic about genetic engineering. Amongst them over 60% answered that they are positive about genetic engineering, and 20 were positive to have GMOs with conditions. 20% were indecisive. The people under 25-year-old were the next most accepting of genetic engineering, then the people between 25-40 years old. The people between 41-65 were the least accepting of genetic engineering although only 12% were negative about it.

However, we need to be careful with the interpretation here since this could be also due to the sampling population since the survey was sent out by iGEM participants to their friends / family and the immediate surroundings of people working in iGEM might be positively biased since they are all in some way related to a person who has knowledge about this subject and also passionate about educating people on it.

Medical Understanding and Interest

We asked participants to rate their understanding and interest in modes of actions of drugs they take on a scale from 1 (not at all) to 5 (I am a scientist in this area).

Graph 2: The general medical understanding and interest by age groups

We received an average rating of 3.2, which indicates a good mix of people from life science and other backgrounds. There is further a clear difference of knowledge about GMO across generation which could indicate gaps in education or outreach programmes.

Based on the previous question the following charts summarise the opinion of those who selected 1 and 5 previously. It is obvious that as knowledge increases so does positivity.

Graph 3: Opinions of people with maximal and minimal medical knowledge

Analysis on Background Knowledge of Participants

Graph 4: Showing where people have heard about genetic engineering from

Most of the people answering our survey have heard about genetic engineering in school (62%). A lot of the people answering our survey have also heard about genetic engineering in scientific publications and popular science media, suggesting that a lot of the people answering our survey are scientists. A lot of the people answering our survey have also heard about genetic engineering through general media showing that genetic engineering is a subject getting a lot of attention in the media currently. As one participant mentioned:

“A lot of people (including myself) do not know that much about it [genetic engineering]. They have probably heard the word in school and some examples, but not really know the consequences or if it is really good or bad.” Therefore, we should be careful in interpreting these results, in combination with our data on the opinions.

Graph 5: Examples of genetic engineering separated by age

We asked all participants to name an example of genetic engineering, so we could estimate where their knowledge came from. We categorised their answers into: ‘agriculture/food’, ‘medicine’, ‘science’ and ‘no/wrong example’. It is interesting to note that each age group has a major area of knowledge: medicine (47.4%) for participants from 25-40; agriculture (65.4%) for participants from 41-65; science (60.0%) for participants of 65+. The group of participants under 25 years old had the most divided answers, but still ‘agriculture’ had a majority with 43.8%.

Opinions on GM Treatments

Graph 6: Examples of GM products that people would use

90% of participants said that they would take a GMO therapeutic, compared to 88% who would consider taking a diagnostic and 78% a preventative GMO. Based on this insight we will market our product as therapeutic in combination with a preventative (not solemnly preventative). 75% stated that they would be comfortable with an internal targeted pill, more than any other delivery method. Only an external gel was more accepted with 77%. Therefore, we decided to have our product delivered via a targeted pill capsule.

Graph 7: Examples of when people would choose a product containing GMO

We further tried to find out what a GMO drug would need to fulfill to replace a traditional treatment. From graph 7 we can conclude that people find effectiveness more important than price when judging whether to use a product containing a GMO. Of all participants, 89% indicated that they could be convinced by a GMO treatment with increased effect at a comparable or lower price, whereas 60% would consider a GMO drug with a lower price, but similar effectiveness. 72% would try a GMO treatment if there is no corresponding traditional treatment for that condition yet. This would be important to implement into the development of our products. It is also interesting to mention that 43% said they would still consider a GMO medicine even without an obvious advantage in effectiveness or price. This, in combination with the overall high response, provides further indication to the positive attitude towards GMO treatment. This might be due to the education people have received on genetic engineering, as one participant highlighted that

“people can be very fearful about new technology and myths are spread. Educating people will benefit society by reducing people’s reservations about GMOs so they can get the most effective treatment possible”.

Conclusions

We have to be careful drawing conclusions since our survey didn’t reach enough people and because it was distributed through social media it has reached a lot of our friends that are studying science at university and are more prone to being positive towards GMOs. However, from our survey, it can be concluded that people have a rather positive opinion towards GMO and are not against using GMO products.

Patient and Public interactions

Following the results from the survey we decided to create two different outreach resources: First, we created one leaflet for the general public that contains information about the general principles GMO and its uses. If you want to read more about this, view our Public Engagement page
Secondly, we designed a leaflet that could be used by C. difficile patients to understand CDI and how we use genetic engineering in greater detail. We received the help of information communication expert Dr Alison Black who has an entire career of experience both in industry and academia in this area. Having previously worked on similar projects, Alison helped us to ensure that the leaflet we produced was able to clearly describe the symptoms and causes of C. difficile infection along with an overview of how our probiotic functions. You can see a copy of the leaflet below.

Using our patient information leaflet, we discussed our project with previous C. difficile patients and asked them a series of questions: 1) From this information would you take our treatment? Is there anything else you would like to know? 2) Would you change anything about the treatment? 3) Would you be happy to take the bacteria in via a capsule? 4) Does everything in the leaflet make sense? 5) Do you understand what we mean by genetic engineering? Would you like any more information about it? The patients’ feedback was very positive with regards to each question, confirming the efficacy of the leaflet in its desired purpose and the patients’ confidence in our safety measures.

At-risk groups

Whilst engaging with patients who had previously had CDI, we also wanted to engage with members of the most at risk group in society to gauge their impression of our project and their opinion towards genetic engineering. Around one third of C. difficile infections take place in over 65s and a disproportionate number of the deaths occur in this demographic; over 80%. These statistics illustrate how vulnerable this sector of society is to CDI. They are however often neglected in discussions of cutting edge technology and bioethics, so we felt it important on a human level to be able to connect with them and take into account their feelings and any concerns they might have. Our discussions proved very fruitful. While we provided information about our project and genetic engineering in general, we received a surprising amount of enthusiastic feedback on our solution. We also wanted detailed information on their opinions regarding the safety measures we had already implemented. Most of our subjects were happy with what we had considered, such as the inducible detection system. When asked about the prospects for treatment, we explained the rigorous safety procedures the therapeutic would undergo. We outlined the further testing we would do, as discussed below and clinical trials that new medicines already undergo, with the additional scrutiny that future GM products would undoubtedly be subjected to.

Therapeutic Development

Dr. Zack Abbott

CEO and Co-founder - ZBiotics

These discussions also led us to consider the future safety considerations we would account for. After discussions with Zack Abbott from ZBiotics we also realised that for long term genetic stability and safety we would use genomic integration. This would ensure that our gene constructs would be far less likely to be transferred to the surrounding microbiota, whilst avoiding antibiotic resistance cassettes.

Dr. Soren Thomsen

CEO and Co-founder - BioMe

As further development of a future treatment strategy we also wanted to survey patients to understand their preference towards different delivery methods. Following discussions with CEO and co-founder of BioMe; Soren Thomson, we decided on two possible delivery methods. One option was using a probiotic milk drink which would be cheaper to produce, however it would also require a higher concentration of L. reuteri as less of it would survive the passage through the gastrointestinal tract. On the other hand, we could use a capsule delivery method, which is more expensive but should deliver our probiotic directly to the large intestine.

After consulting with previous CDI patients, the majority of patients preferred a pill, as it felt “more like a treatment” and would find it easier to administer. Some patients also asked us how long the bacteria would survive in the gut and thus how often the therapeutic would have to be administered. After a proof of concept, we would hope to study this in an animal model system before we would provide this dosing information for clinical trials and potential patients.