Integrated Human Practices

Integrated Human Practices has been key in the development of Esther. Through the opinions of four different sectors - research, public stakeholders, legal authorities and industry - we were able to get invaluable feedback which enabled us to better shape our idea. Later on, they helped us evaluate the market potential of our product and the legitimacy of it as an alternative to antibiotics.

Brainstorming

At the beginning of our journey, we arranged a brainstorming session to look for problems that affect society and that could be solved using synthetic biology. We divided ourselves into small groups and each had to select a problem that they would focus on. This was followed by another brainstorming session to come up with possible solutions to tackle these problems. During this time, our team members contacted multiple experts, which helped them shape their project proposals. Many interesting ideas were brought to the table: an enzyme to degrade microplastics, a diagnosis system for early detection of multiple sclerosis, a molecular system to determine bacterial infections... With so many different options, it was difficult to pick just one.

We decided to invite a panel of experts who could provide us an unbiased viewpoint on each of our proposals. The panel included senior researchers at Karolinska Institutet, Stockholm University and KTH Royal Institute of Technology, as well as members of SGEM (Stockholm iGEM alumni network). The different members of our team had to present and defend their projects in front of these experts using the NABC approach, developed by the Stanford Research Institute to frame the development and communication of innovative solutions.

After presentations, the experts gave us feedback that helped us evaluate the different proposals and select one: an efficient delivery system for phage therapy.

Our team decided to work on this project for several reasons, that were also pointed out by the experts. First, it focuses on solving an issue that affects not only the Swedish society but also all people worldwide - the rise of antibiotic resistance. Second, it takes a sustainable approach, since new phages can be easily isolated from natural resources. It would cut down on costs that are usually required for the development of new antibiotics. Third, our experts appreciated that it was a novel idea, which also motivated us to continue on this road.

After brainstorming, we interviewed Erik Haeffler, the Vice President of Manufacturing Services & Head of Sustainability at Recipharm AB, the leading Swedish pharmaceutical contract development and manufacturing organization. Learning about the current struggles to develop new antibiotics helped us corroborate the need for an alternative approach, and validated our idea.

Project Development

Having our goal in mind - to create a delivery system that would increase the therapeutic efficiency of phage therapy - we started to develop our project. Our idea was to create a switch that would keep the phage dormant inside the vehicle bacteria, but that we could activate after it had reached the site of infection. The idea seemed great, but where do we start?

Our team started by contacting Anders Nilsson, one of the very few researchers in Stockholm working with bacteriophages, and Elisabeth Haggård-Ljungquist, a retired professor and scientist who had spent her career studying the P2 temperate phage. Their insights helped us better understand the genetics of bacteriophages and how they could be manipulated for our own purposes. In particular, it got us interested in bacteriophage P2, which we thought we could successfully use in our project. This led us to the development of an engineered switch.

Ethical Considerations

During brainstorming and project development we ran into some ideas that were protected by patents. Are we allowed to work with them? Could we use them to develop our iGEM projects? And how do we make sure our project meets the ethical standards? We did not have the answers to these questions, but we were willing to learn. We also wanted to allow other students outside of iGEM to learn about these topics, so we decided to organize an event which we called Bioethics and Biolegislation. We invited Joanna Applequist, a European Patent Attorney from Valea AB, and Jesper Ahlin Merceta, an expert in Bioethics, from KTH Royal Institute of Technology, to be our guest speakers. This event helped us understand that we were indeed allowed to research topics that were patented since the patent only prohibits to sell ideas that belong to others. Furthermore, we learned about the trade-off between biotechnology and society, and we understood that when trying to bring a new treatment out to society, we need to be very careful and analyze properly the environmental and social implications.

Safety Considerations

Because of the high risk of contamination and strict regulations, we were not able to use bacteriophages in our laboratory. Therefore, we came up with an alternative - to create a Model Plasmid that would behave as our bacteriophage and would still allow us to test our switch.

The safety of our product was something we did not want to compromise. This was also to fulfill the guidelines of iGEM Human Practices which expect from a project to be responsible and good for the world. When reading about the safety concerns of phage therapy, we realized that temperate phages are not used for this purpose, because they may potentially contribute to antibiotic resistance through horizontal gene transfer. However, we came across a news article that claimed the use of an engineered temperate phage to treat a patient in the US. Curious to learn more, we talked to Graham F. Hatfull, the principal investigator of the study, who provided us more documentation about how they did it. (1) His input helped us to understand that our plasmid switch was safe to use, as we were also using a phage that lacks the repressive protein. (2)

Furthermore, we were also given the opportunity to discuss the safety of Esther once released to the environment or the water system during the World Water Week. Researchers, policymakers, business and other stakeholders from all over the world get together to discuss the future of our most valuable resource: water. Our team and the iGEM Stockholm 2018 team was invited to participate in a panel discussion called "Water, Health, Antibiotic Resistance: Probing One-Health and Rights-Based Approaches", and we were also able to showcase our project in a booth.

What time is it? Is summertime!

As the wet lab team was trying different cloning techniques, our Integrated Human Practices team contacted multiple stakeholders and corporations.

Meeting the authorities

During this period, we contacted (Platinea), a multisectoral collaboration platform to preserve and enhance the value of existing antibiotics. The platform consists of 15 partners from academia, authorities, healthcare, and industry across Sweden. We discussed with the director Enrico Baraldi our project and its potential use of phage therapy in the Swedish healthcare system, as an alternative to antibiotics. We believe this discussion helped us start an important dialogue about the necessity of phage therapy and we received a very positive response. It also gave us a new perspective on our project. First, completely replacing antibiotics with phage therapy was very unrealistic and unnecessary, as antibiotics were very standardized already and presented multiple benefits. Therefore, we changed our strategy and focused on promoting the correct use for both antibiotics and phage therapy, as these two treatments can complement each other.

Learning from iGEM Munich

As we are now aware that Sweden is more than ready to support the development of new treatment approaches for bacterial infections, we wanted to understand the necessity of informing the public about it. Antibiotic resistance and its implication is a subject well known among our society, as demonstrated by the results of a questionnaire from the (iGEM Munich 2018 team), but phage therapy remains unheard of. A member of our team, Itisha Adhikari met iGEM Munich team during summer, to find out more about their rationale behind this questionnaire. As an outcome of this meeting, we all concluded that public education is of great importance for the successful implementation of new treatments.

Interviewing experts for the documentary

With this in mind, we decided to tackle the lack of awareness by creating a documentary that could be easily understood by people from different backgrounds and ages. The purpose of this documentary was not to promote our iGEM team or our project. Instead, we focused on providing reliable information in the form of interviews, so that the general population could learn more about phage therapy. We believe that this initiative should be continued by future teams working with phage therapy so that the information can spread to other countries and more people. Read more about our documentary!

By interviewing people for the documentary, we learned new things about phage therapy ourselves. It helped us understand the necessity of collaboration between researchers and clinical institutions in order to be able to test the clinical efficacy of phage therapy.

Playing with the public stakeholders

Creating a documentary and speaking about phage therapy on TV were great starting points to raise awareness about Phage Therapy. But we wanted to spark curiosity within people, and give room for questions and conversations, so we left the 2D TV screen and went out to the streets! To make it fun, we designed a card game in which people would have to select images that would associate with a topic we proposed. The drawings and the topics were all related to Human Health, Antibiotics and Phage Therapy. We called this game Pixid. You can flip it upside down and it will still be the same name, Pixid!

Pixid was a great game to start a dialogue between our team and the general public. While playing, we proposed the topics in the form of questions, and let the players discuss between them or in teams what images they associated with the question. In the end, we would ask why they chose that specific card and tried to understand their thought process. There were no wrong or right answers, only the opinion of the general public.

We believe these activities are important, not only because it helps us understand the opinion of the general public regarding our product, but also because it helps people understand that science can be accessible for everyone, and that everyone can participate in the making of science.

It might be Fall, but we rise up!

Let's talk business!

Our team was incredibly pleased to speak with Minmin Yen, CEO, and founder of PhagePro. Her start-up developed ProphaLytic-VC, an orally dosed preparation of bacteriophages that are specifically targeted towards epidemic strains of cholera. She has recently been included in the 35 innovators under 35 list.

Thanks to Minmin, we were able to learn more about how a research project can become a startup, and what obstacles she encountered when marketing and selling phage therapy. Inspired by her story, we analyzed what would be the next steps for our project to become a startup.

We scheduled a meeting with Drivhuset and the Stockholm University Innovations Office, who evaluated Esther and proposed us two main focus points, that are essential at the beginning of any startup: Intellectual Property and Prototyping. In other words, show your idea, protect your idea!

Protect your idea

Intellectual Property and its modus operandi was a big question mark for our team. Previously in May, we organized a Bioethics and Bio-legislation event (link to Education Human Practices), for which we contacted multiple experts. Even though this event had been initially created to inform students about the crucial role that these two fields play in research and product development, we ended up finding the information useful for the development of our own start-up.

For evaluating the novelty of our idea, and to understand the implications of Freedom to Operate (FTO) and infringement, we spoke with Joanna Applequist, a European Patent Attorney at Valea AB. With her help, we learned what the requirements would be for patenting Esther. Later on, we discussed this idea with the SU Innovations Office and Drivhuset, who could provide us with grants to perform the first steps for filing a patent. However, given the current state of phage therapy in Sweden and in Europe, we saw no immediate market benefit, as it is not regulated like common drugs in most European countries. In those countries where it is - France, The Netherlands, and Belgium- it is only given as a compassionate treatment, which would not produce enough benefit to keep up a patent for the next upcoming years.

Show your idea

Prototyping is a pivotal step to bring out a product to the market, as it allows you to test how the user will perceive it before investing high amounts of money in manufacturing and distributing. But how do we know this? Truth is, we didn't, but we knew that if we wanted to bring Esther out from the lab and into the market, we needed the experts' help.

So, we collaborated with iGEM Uppsala to organize a Bioentrepreneurship event called Bench to Bedside. This event was held on September 18th, 2019, at Karolinska Institutet. Our keynote speaker was Anna Svantes, the business developer of Organofuel AB, Sweden, who discussed her journey and how her team conceived the start-up. Their business idea was introduced, and the science behind their technology was discussed briefly. The goal was to provide inspiration to our audience on how to bring their scientific ideas to life and a well-functioning business. As well as promoting the entrepreneurial and innovative side of science beyond iGEM.

At the heart of the framework for innovation is design methodology, the Double Diamond – a clear, comprehensive, and visual description of the design process. The latter session, lead by Design Thinking Coach Cecilie Hilmer, was focused on design thinking and learning how we can use the Double Diamond Model of Design Thinking. To make a product that would fit in well into a user-driven society, the importance of assessing the problem in-depth, to fully understand the goal of our product, and prototyping to get useful user feedback. Later, we went on to create basic prototypes of iGEM projects and gained some valuable insight on how to bring our product to existence in an effective way. It was a very creative and fun afternoon, where both iGEM Uppsala and iGEM Stockholm were able to obtain feedback about how to further mold their product to be successful in the market!

SynthEthics

An interview with a policy expert from the Swedish Pharma Association, Bengt Mattson, led us to realize that regulations surrounding synthetic biology and the use of GMOs are the greatest barriers for projects such as ours. These regulations are driven by the current ethical points of view in society. We realized that we might need to take some special ethical considerations before selling "Genetically Modified Microorganisms". In collaboration with iGEM Lund, we investigated the current situation to formulate questions for the general public and experts. This would enable the collection of insights from the general public as well as researchers specialized in this area. The questions were designed differently according to the target group. For the ease of public survey, we made yes/no questions and elaborative questions for the experts in the field. The objective of this project was to initiate a legislative draft that could take into consideration the ethics which are not standardized and, therefore, a limiting factor in the use of GMOs and synthetic biology.


The feedback obtained was vital not only for the future of synthetic biology but also regarding the future launch of Esther into society.

To read more go to the SynthEthics project page!

Our trip to Georgia

After speaking with researchers, policymakers, and business representatives, it was time to observe how Esther would work in a hospital set up. Unfortunately, phage therapy is not provided as a treatment in Sweden, which is why we tried our best to contact people from the Eliava Phage Therapy Centre in Georgia. After months of trying, two members from our team, Itisha and Nerea, were finally able to travel to Georgia to visit the Eliava Phage Therapy Centre.

Eliava Phage Therapy Centre has been the largest global center of phage expertise for more than 80 years. They also showcase a success rate exceeding 80% in treating patients with multi-drug resistance from over 65 countries, including Canada, USA, France, UK, Germany, China, India and many more. This motivated us to find out what and how exactly were they so successful in doing so and where Esther can fit, as a product, in aiding their treatment.

We visited the clinic where patients are consulted, and interviewed a Dutch patient who had traveled from the Netherlands to get treated for a foot infection. Misdiagnosis and overconsumption of wrong antibiotics had led him to suffer from an antibiotic-resistant pathogen, and the risk of losing his leg forever. He expressed his excitement with the treatment to us, as just after 2 days of receiving a phage cocktail, his swelling had considerably reduced. He concluded his story by saying that he would very much like to see this treatment being accessible in European countries, which motivated us to continue the journey that we had chosen.

Speaking with a young doctor, Mariam Dadiani, we learned that its not just about providing a product but training physicians to be more skilled in diagnosing and practicing phage therapy. She had been educated about this treatment during Medical School, as a student in Georgia, and she said that other physicians were aware of this treatment as well. Furthermore, she helped us to understand the importance of the right diagnosis and what the process of receiving Phage Therapy at the Eliava Center looks like for an international visitor.

We visited research labs, where they screened phages and patient samples, which resulted in insights on how we could extract our phage strains by using simple yet sophisticated techniques like bacteriological essays and phage sensitivity testing. They used these results to not only provide the patient with an appropriate cocktail of phages but simultaneously add these strains to the most extensive phage library currently available.

The magnificent phage library stored literature from eminent phage researchers from all around the world for more than 100 years. This only validated our initial testimony that phage research has existed for around a century and only needed to be revamped.

Finally, we met the Business Manager, Nikoloz Ratishvili, and the Director of the Eliava Institute, Dr. Mzia Kutateladze, who explained to us the scope and the market potential of phage therapy. They supported our project with extremely crucial feedback on the use of temperate phages. They believe that natural phages work well now, but genetically modified phages may bring an array of improved functionalities to the table. They were particularly impressed with our efforts in the public engagement and education sector since awareness about phage therapy is the biggest challenge, according to them.

Final conclusions

Integrated Human Practices was a key component of our project. The information, feedback, and suggestions we obtained from the different experts, policymakers, company representatives, and public stakeholders helped us shape Esther. From brainstorming, to project development, to safety checks, to business development and product delivery, this journey would not have been possible without our Integrated Human Practices team and the valuable conversations they had with all the players mentioned above. We would like to thank everyone that took a few minutes, hours, and even days to help this group of students turn their idea into a tangible project.

The lessons we learned during our events, interviews, and trips not only helped us develop Esther, but they also helped us to develop ourselves as future scientists, business employees, and policymakers.

References

  1. Dedrick RM, Guerrero-bustamante CA, Garlena RA, Russell DA, Ford K, Harris K, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med [Internet]. 2019;25(May). Available from: http://dx.doi.org/10.1038/s41591-019-0437-z
  2. Dedrick RM, Guerrero CA, Garlena RA, Pinches RS, Cornely K, Hatfull GF. Mycobacteriophage ZoeJ : A broad host-range close relative of mycobacteriophage TM4. Tuberculosis [Internet]. 2019;115(December 2018):14–23. Available from: https://doi.org/10.1016/j.tube.2019.01.002