Team:Freiburg/Human Practices
Integrated Human Practice
Resistance of microorganisms against conventional antibiotics is rapidly increasing and major companies end their antibiotics research 1, therefore we drift towards an “post-antibiotic era”, if no urgent actions are taken. In many countries such as Tanzania, Vietnam and Nigeria, antimicrobial resistance is already a serious problem 2. We contacted and engaged with the public as well as various experts from academia and industry. In an interactive diagram, we portrayed all events that shifted our project to its final form. With the helpful input and feedback of many people from companies, research institutes and daily life, we advanced from therapeutic application to laying the foundation for the amazing abilities D-Amino acids provide.
Click on any of the boxes to find out more about a specific part of our Integrated Human Practices.
Summary
The inputs from Prof. Willbold and, yet again, further literature research convinced us that we want to develop a D-peptide inhibitor against PSMα3. Gaining knowledge about D-peptides and their use as therapeutics also led us to discover more interesting properties of D-amino acids themselves. We encountered fascinating applications like modifying spectral properties or stabilizing proteins5 and discovered many possibilities for in vivo usage of D-amino acids8. Maybe the potential of D-amino acids lays not just in the therapeutic field but is more foundational?
Summary
After visiting the Peptide Center Ulm we were fully convinced to work with peptide therapeutics. However, while establishing our workflows in the laboratory, we picked up on the advice of Prof. Münch and Dr. Rosenau and informed us about D-peptides. They appeared to have tremendous potential, which is not fully discovered yet. Thus we asked ourselves, if we should shift our efforts from working to find a L-ligand to finding a D-ligand. Therefore we contacted Prof. Willbold an expert on the field of D-amino acids.
MRSA! Peptide Therapeutics?
After meeting with Mr. Häcker, we researched for possible targets. After, yet again, going through papers, literature and brainstorming sessions, we decided to address the problem of methicillin-resistant Staphylococcus aureus (MRSA), which refers to the group of gram-positive bacteria. MRSA can be found everywhere, where antibiotics are used regularly. In German hospitals about 20% of the Staphylococcus aureus bacteria are multi-resistant. While many people, who carry MRSA bacteria on their skin or mucosa do not have any complaints, MRSA can have severe effects for people with a weakened immune system. Seniors, infants and people with a weak immune system. Especially seniors and infants are at risk to have a severe course of the disease3. People can easily protect themselves, by careing about their hygiene. We discussed many possibilities to tackle the MRSA crisis, for example with Phage Therapy. Then we got the idea to use peptide Therapeutics, which seemed to be an exciting and viable option. We agreed to establish ways to find a ligand, which can be used as peptide therapeutics, to reduce the toxicity of PSMα3. Hence we chose to visit experts within that field, while informing ourselves about the advantages and disadvantages of peptide therapeutics.
Actions
- Visit experts at the Ulm center for Peptide Therapeutics (U-PEP).
- Start preparing experiment
Summary
Our decision to choose a topic with a major impact on society was reinforced after engaging with the public. With new we analyzed the emerging problem, we realized that we have to act upon this upcoming crisis now. If there is no solution found by 2050 every three seconds someone would die from multi-resistant bacteria, according to the review on Antimicrobial Resistance (AMR report) This is a global problem which affects every aspect of our life and will progress into a huge economical problem. Besides this worrying development, more and more pharmaceutical companies stop financing their antibiotic research and development2. The AMR report predicts a total gross domestic product (GDP) loss of more than 100 trillion Dollar1, due to the damage inflicted by multidrug-resistant bacteria. Taken together we decided to focus our project on taking a step towards a solution against this development.
Summary
After getting to know each other, we quickly got to work and started brainstorming possible project ideas. Many topics were discussed, for example building a light-inducible cell printer, but with each idea we discussed we realized that our project has to be a foundational asset to not only the iGEM but the SynBio community. Thus - with the valuable input of our supervisors - we dug deeper into literature and kept looking for a fascinating project.
Lessons
- During the brainstorming phase we identified various aspects of an successful project. We started thinking of ways on how to incorporate society into the progress of finding our project.
Actions
- We dug deeper into the literature, read countless papers and had countless brainstorming sessions.
- We decided that besides the valuable input from our supervisors we wanted to engage with the public to find a project that is a pressing issue in society and science.
Summary
After reflecting on the discussion with the high school students, we realized that many questions were influenced by the headlines in recent years (for example the “CRISPR babies” in China 2). We asked ourselves how polarizing headlines affects the way people evaluate synthetic biology. To answer this question, we went on the streets of Freiburg to demonstrate how over-dramatisation through media can lead to misconceptions of scientific topics. With the interviewed people we discussed in one on one conversations, possibilities and future potential, that synthetic biology may enable. Some shared new possible ideas with us, which gave us more input for our project search. Afterwards, we handed them a flyer, which gave a brief easy-to-understand summary of current topics in synthetic biology and explained the concept of iGEM. The personal stories and opinions of the interviewed project encouraged us to create a project, which has the potential to address a problem that affects everyone in our society and that can be solved by science and society together - hand in hand.
Lessons
- Choose a topic that has a direct social impact.
- The public opinion must have an impact on the future of SynBio.
- Provide an easy way for anyone to engage in science and our project.
Actions
- Encouraged us further to work on a problem that affects society.
Summary
As a scientist, one doesn’t necessarily think about public opinions while developing new biological tools or solutions that help our modern-day world. We asked ourselves how is synthetic biology seen by the public? What do people associate with this term? Have they ever heard of it? In order to shape a common future for everyone, the dialogue between science and public is crucial. We reflected on new ways to communicate and discuss science aiming to arouse interest of anyone regardless of their age and social or educational background. We agreed to engage discussions with ethicists, scientists, teachers and most importantly the general public. We went on the streets and captured the reaction of the public regarding polarizing headlines in order to engage in a dialogue afterwards to discuss the chances, but also potential dangers of synthetic biology
Lessons
- The future will be shaped by synthetic biology. This process needs to be formed and lead by all people, not only scientists
- We included the opinion of different status groups during the progress of our project
Actions
Summary
During our brainstorming phase, we had the chance to discuss the possibilities of synthetic biology with a class of high school students. We aimed to arouse their interest in synthetic biology and to reflect on any misconceptions they might have due to the ambiguous public perception of synthetic biology. We discussed ethical aspects of synthetic biology and genetic engineering. Additionally we highlighted the possibilities that high school classes can also join iGEM, which really resonated with them. Click /here/ to find out more
Lessons
- The importance of society in scientific debates, regardless of age, should not be underestimated.
- Inspired us to further research misconceptions of Synthetic Biology due to polarizing effects of tabloid media.
Actions
- Agreed to seek further inspiration by working with the public.
- Started to lay a foundation for our public engagement .
- Offered our supervision/help, if they would want to start an high school iGEM team.
Summary
On one hand we gathered a lot of information due to literature and reports about multi-resistant bacteria, on the other hand we wanted to hear from experts with direct experience regarding this topic. To gain additional insights and perspectives, we met with Prof. Dr. Häcker, president of the German Society for Hygiene. While the rise of multidrug-resistant bacteria is an upcoming global crisis, he stressed that the situation differs from country to country. Countries with a working health care system are fortunate enough to be able to prevent the spread to a large degree at this particular moment. However, statistics does not matter, when it comes to the individual person. Prof. Häcker shared his clinical experience with us: “I have seen cases where we literally did not have a single antibiotic left and then we just hope that the patient's immune system is efficient enough to fight the infection.” We further discussed the critical conditions regarding multi-resistant germs in the developing world and the retreat of many pharmaceutical companies in this area. As we asked him, if peptide therapeutics are an alternative to antibiotics, he mentioned as their disadvantages due to the required high dosages.
Lessons
- Multi-resistant bacteria are already a problem for countries with a weak health care system.
- TPeople are dying because of this situation at this very moment, we live in a privileged situation.
Actions
- Final decision not to shift our project: We will help provide a solution against multi-resistant bacteria.
Summary
Peptide therapeutics development underwent rapid acceleration within the last years (REF). Economically a market increase of 9.1% from 2016 - 2024 is expected4. After gathering information about the advantages and disadvantages of peptide therapeutics, we met separately with Prof. Dr. Frank Münch and Dr. Rosenau, founders of the Ulm center for peptide therapeutics. Prof. Münch underlined the advantages of peptide therapeutics: “If we can make peptide therapeutics orally available, then Peptide therapeutics will be the medicine of the future - I am convinced of that.” Münch briefly mentioned how D-amino acids could be an option to bypass many of the disadvantages of L-peptides. We further discussed economical aspects and options, how to turn your research into economical value. Dr. Rosenau, who works with phage display and mirror-image phage display, discussed the advantages of those methods with us. Regarding our project he reinforced us to work with peptide therapeutics: “I do believe one of the main focus points will be targeting of antimicrobial resistance. Peptide therapeutics promise to be a relatively simple approach to generate new reserve antibiotics. At this moment the fight against multi-resistant bacteria has come to a crisis and the World Health Organisation (WHO) published a warning list, including Pseudomonas and MRSA”. Prof. Dr. Münch, as well as Dr. Rosenau, recommended us to visit Prof. Dr. Willbold, founder of Priavoid, a company, which aims to bring an all D-peptide therapeutics on the market.
Lessons
- Consider economical aspects in our project.
- Peptide therapeutics have immense potential, but also restrictions.
- Possible ways to overcome those restrictions may be D-peptides.
- Reinforced our aim to tackle antibiotic resistances.
Actions
- Start establishing phage display.
- Start setting up In-Silico models to simulate dockings and bindings.
- Contact Prof. Willbold.
Summary
Prof. Willbold is cofounder of Priavoid. Priavoid developed an all-D-peptide therapeutic against Alzheimer disease, which entered clinical trials already5. He emphasized the advantages of D-peptides: ”D-peptides combine the advantages of small molecule compounds with the advantages of therapeutic antibodies”. He explained that their drug candidate has a way higher half-life and thereby overcomes one of the biggest disadvantages of peptide therapeutics: “After 24 hours we observed that 90% of the D-peptides were completely unmodified [...]. The L-versions of those peptides were degraded in seconds in analogous experiments.” Also his drug candidate can be administered orally! Prof. Willbold confirmed that it’s possible for us to do a mirror-image phage display and work with D-amino acids.
Lessons
- It’s possible for us, to work with D-amino acids
- Advantages of D-peptides.
- Learned what we need to consider, if we want to start a company.
Actions
- Chemical synthesis of targets and ligands.
- Establish a phage display
- Develop in-silico methods to find D-Ligands for possible targets
Summary
To gather more expertise about mirror image phage display, chemical synthesis and the potential of D-peptides we contacted Prof. Kent from the University of Chicago and Prof. Kay from the University of Utah. They shared their knowledge about the methods with us and helped us to decide, which kind of chemical synthesis is possible for us. Furthermore, Prof. Kay kindly provided us as sample of IZN24, a D-peptide he’s working with. This enabled us to practice mirror-image phage display, and to further improve experiments and discover more possibilities of D-amino acids in the lab. With another D-Peptide we could demonstrate the general protease resistance of D-Peptides
Summary
We had the chance to attend the Q-Summit at the University of Mannheim. Q-Summit is a meet-up between start ups, investors, major companies (for example Facebook or PwC) and young talents. While we had an amazing experience to talk with other young talents, who will shape the future, we had a lot of lively discussions about the possibilities, which synthetic biology may offer and how it may impact the biotechnology sector in the future. Furthermore, we had the chance to pitch our project in front of hundreds of people and we met Anja Feldmann from the company BASF SE, world biggest chemistry company, with whom we agreed to stay in touch to cooperate further.
Lessons
- New possibilities to find partners and funding, in case we commercialize our project.
- First pitching experience for our project
- Better understanding how industries, startups and academia can work together.
Actions
- Establish contact with BASF.
Summary
After meeting Mrs. Feldmann at the Q-Summit, we stayed in touch and BASF offered us to present our project as soon as it’s close to finishing. We took this chance and presented our project in front of leading experts of BASF. After a Q&A session we realized our project could have further impacts, for example by applying it on lifestocks. BASF confirmed that we should expand our project after iGEM and urged us to stay in touch so we can cooperate further. This motivated us to consider, if we should patent our ligands.
Lessons
- Further potential markets for our Project.
- Our project is commercially interesting for major companies.
- Let us to consider if we should partner up with “big company”.
- Critical Input for our presentation in Boston.
- Consideration of filing a patent.
Actions
- EHold contact.
- Restructure presentation
- Filed a patent
Summary
Basel Life is Europe's leading congress in the life sciences, showcasing cutting edge science and technology. This year the topic peptide therapeutics was a focus of Basel Life, amongst other emerging scientific fields. Since this is an essential part of our project it was inevitable for us to attend Basellife where novel innovations meet inspiring ideas to tackle modern-day problems. We had the chance to learn of the newest developments in the field and to exchange ideas with renowned scientists who have dedicated their research to the identification, optimization and production of peptide therapeutics. Amongst other scientists Prof. Dr. Dieter Willbold, Walter Mier and Prof. Anna Maria Papini gave inspiring insights into their work advancing the potential of peptide therapeutics. Our visit showed us how broad the field of peptide therapeutics really is and how many possibilities peptides offer for clinical use. Target-binding peptides can be applied as inhibitors for enzymes, but also as radioactively labeled probes that bind specifically to tumor tissue expressing a certain marker. Those so called “theranostics” can be applied as therapeutics as well as for diagnostic use (Melpomeni Fani, University Hospital Basel). Furthermore we learnt about the latest progress in SPPS peptide synthesis, how to increase solubility of ones products using backbone protection groups (John Offer, The Francis Crick Institute, London) and about a new, eco friendly solvent which additionally reduces side-reactions (Jon Collins, CEM, Matthews). After an inspiring day with lots of fascinating lectures we returned to Freiburg with many ideas on how to improve on our project.
References
[1] https://www.tagesschau.de/investigativ/ndr/antibiotika-pharmakonzerne-101.html, visited 10.18.2019, 00:11am, UTC+1
[2] Hendriksen, R., et al. Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage (2019). Nature Communications. Volume 10: 1124
[3] Cyranoski, D. The CRISPR-baby scandal: what’s next for human gene-editing (2019). Nature. Volume 566: 440
[4] https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf visited 18.10.2019, 6:12 pm, UTC+1
[5] https://www.infektionsschutz.de/erregersteckbriefe/mrsa/ visited 10.18.2019, 06:09 pm, UTC+1
[6] https://www.transparencymarketresearch.com/pressrelease/peptide-therapeutics-market.htm, TMR Analysis of 2017
[7] https://www.gesundheitsindustrie-bw.de/fachbeitrag/aktuell/peptide-als-wirkstoffe-kommen-allmaehlich-in-fahrt visited 10.15.2019, 3:22 pm, UTC+1
[8] Ma, H., Liu, N., Shi, S., Wang, S., Chen, Y. (2015). Genetic incorporation of d-amino acids into green fluorescent protein based on polysubstrate specificity. RCS Advances
[9] Genchi, G. (2017). An overview on D-amino acids. Amino Acids
[10]Tullo, A. H.C&EN’s Global Top 50 chemical companies of 2018 (2019). Chemical and Engineering News. Volume 97, Issue 30
