Human Practices

Overview

▶We have conducted all our activities with the social implementation of our project in mind. To implement a project in society, it is necessary to carefully and imaginatively demonstrate that the project is reasonable and responsible. From the beginning of the project until just before the wiki freeze, we constantly brushed up on the project based on the Human Practice philosophy of iGEM.

▶Throughout our activity cycle, Human Practice feedback was instrumental in the following: 1. Defining the Project’s Overview, 3. Antidepressant Compounds Production, and 5. Project Sharing and Discussions.

We, Japan-United, are an iGEM team that was founded in September 2022. Initially, we were just a group of high school students with enthusiasm for synthetic biology and did not even have access to a lab. However, we have consistently followed the Human Practice philosophy of iGEM from the beginning. We have two main points in mind when conducting our Human Practice activities:

1. Engage with a wide range of stakeholders and exchange views

2. Reflect and improve on lessons learned from projects

In the first point, we gained insights that we lacked by engaging with more stakeholders, including experts, companies, and the general public, and collected feedback on the project.

Second, we used the insights and feedback we gained in the first point to improve the quality of the project by iterating and improving the project.

1.Define the Project’s Overview

1-1. Survey on Depression

▶As a Japanese team, we focused on depression, a severe social issue in our country.

▶We surveyed the current status of depression in Japan. We conducted this survey on the general public and medical professionals.

1-2. Professor Masayuki Su’etsugu

▶ When we learned about the challenges of antidepressant therapy, we began to think about the possibility of using_ E. coli_ to produce naturally occurring antidepressants cost-effectively and stably.

▶ We presented our project to Professor Masayuki Su’etsugu, a well-known synthetic biologist in Japan, and received technical feedback.

A literature review and 1-1. “Survey on Depression” has highlighted the challenges of existing antidepressant therapies. The primary antidepressant treatments are pharmacotherapy, which has severe side effects, multiple medications, and psychotherapy, which is expensive.

We turned our attention to naturally occurring antidepressants. A common characteristic of many naturally occurring antidepressants is that they combine a certain level of antidepressant efficacy with low side effects. As a result of our literature review, we focused on ginkgolide, a terpenoid found in Ginkgo biloba. We began to consider the possibility of stably producing ginkgolide at low cost using E. coli.

Not being technically inclined, we asked Professor Su’etsugu for technical feedback. We were informed that production in E. coli would be complex due to the presence of CYP450 in the biosynthetic pathway.

At the same time, we received the feedback, we negotiated with Professor Su’etsugu to use his laboratory as our research base, and he readily agreed. He has been providing us with technical advice and support for a year.

1-3.Akaito, Limited①

▶ We focused on saffron (Crocus sativus L.) as a naturally occurring antidepressant instead of ginkgolide.

▶ We have learned that Japan produces high-quality saffron; we held discussions with a Japanese saffron farm, Akaito, Limited.

We learned about the world’s current state of saffron production, including the forced labor of children and women and the difficulties of its cultivation. We also discussed the details of the project, including the need to expand investigation on a global scale and the enormous costs involved in producing pharmaceutical products.

These discussions convinced us that there is great potential for producing antidepressants (crocetin, crocin, and picrocrocin) derived from saffron in E. coli.

2.Antidepressant Compounds Production

2-1. Dr. Manabu Saito

▶ We started looking for ways to make antidepressants available to the general public. We had discussions with Professor Manabu Saito, who works closely with depression sufferers and has deep expertise in this field.

We discussed with Dr. Manabu Saito, a psychiatrist and professor at Hirosaki University, how to provide the antidepressants we produce to depressed patients. During our discussion, she pointed out that Japanese psychiatry is lagging behind and that it is best to provide a means of self-control for depression, as well as the problem of taking multiple medications. In response, we decided to offer the product as a snack that anyone could eat as a means of self-control instead of the pill we had initially envisioned. Given the lack of established self-control measures for depression, the fact that patients with mild depression have difficulty recognizing their symptoms, and the fact that people who become depressed can prevent it, we were convinced that this method, if realized, would reduce the number of depressed patients and people who will become depressed in the future. We also learned about the costs of existing treatments and were able to correct some of our misconceptions about depression.

2-2. Mr. Hayato Kano

▶ We decided to provide antidepressant substances for self-control and began to think about what products we could easily consume.

▶ We discussed with Hayato Kano, CEO of RelieFood Inc., who is developing allergen-free products.

We discussed with Hayato Kano, CEO of RelieFood Inc., who is developing the allergen-free product, to learn what is necessary and what we need to pay attention to when offering the product as a confectionery. We discussed the product, such as what kind of candy is suitable for self-control and how to produce it, as well as legal issues, such as whether ingredients produced with E. coli can be sold. During our discussion, we decided to market the product in cookies. This decision was influenced by several factors: the substances are not water-soluble, cookies are palatable even for individuals experiencing depression, they are simple to produce, and they can readily incorporate the desired ingredients. We came up with a specific direction and schedule. Through these activities, we were able to determine our ultimate goal: a means of self-control.

3.Project Sharing and Discussiions

3-1. Akaito, Limited②

▶ We had another discussion with Akaito, Limited as our research at the wet lab progressed, and we began to form a concept of the final product.

▶ Akaito, Limited has the expertise to sell dried saffron. We discussed the barriers to considering the social implementation of the product.

The second discussion focused more on entrepreneurship. We learned about the differences between dietary supplements, functional foods, and pharmaceuticals, the process of commercialization, and the respective markets and regulations. Through these discussions, we decided to produce cookies as an available food as no clinical trials and strict rules are required. Although the benefits of saffron have not been certified by the FDA, many studies have shown the relationship between saffron and depression. We concluded that the data is sufficient to market the product as a functional food rather than a drug.

3-2.Pioneer EcoScience Co., Ltd.

▶ We began to formulate assumptions about social implementation. We then decided to hold discussions with companies that have experience with the hurdles of implementing genetically engineered products.

▶ We held discussions with Pioneer EcoScience Co., Ltd., the first company in the world to commercialize genetically modified tomato seeds successfully.

We had in-depth discussions on the commercialization of our product. We learned about the regulations for genome-edited and genetically modified foods in Japan and abroad and the different production methods for the experimental stage and commercialization. It was also pointed out that making the story more transparent and more understandable to the general public is essential, so we improved it to make it more detailed and more accessible to comprehend.

3-3. Fermelanta, Inc.

▶ The hurdles to the social implementation of genetically modified products vary from case to case. We discussed with Fermelanta, Inc., which aims for the social implementation of material production by microorganisms, similar to our project.

Our discussions focused more on social implementation. We also discussed the differences between the material production methods used in the R&D phase and the social implementation phase, the time and steps required for commercialization, and the laws and regulations in Japan and other countries that were raised in our discussion with Pioneer EcoScience Co.We were also able to learn about the heat process to prevent DNA from remaining in the product. Through these discussions, we moved beyond the experimental stage into the prospecting social implementation stage.

3-4. Mr. Tatsuya Ono

▶ We did a final touch on our project by having discussions with companies that have successfully implemented material production using microorganisms, similar to our ultimate goal.

We discussed social implementation with Mr. Tatsuya Ono from the Business Development Department of the Green Earth Institute, Inc.

We discussed the current status and future potential of synthetic biology and genetically modified organisms, in addition to entrepreneurship issues such as calculating the cost of substances produced by microbial fermentation and the details and time length from the start of research to social implementation. Although we found that we could achieve our goal of cutting costs by using E. coli without purification, it was pointed out that we may need to consult with the relevant ministries and agencies to ensure the safety of consuming “genetically modified E. coli.” Given that many individuals have raised this point, we believe it’s prudent to communicate this aspect transparently and offer the product exclusively to those who provide informed consent.

3-5. Discussion of Genomic Ethics

▶ This hypothesis drove our project: By making E. coli chromosome-free, we could lower the existing regulatory hurdle focused on “growth.”

▶ We tested our hypothesis through discussions with legislators and researchers.

We held discussions with researchers specializing in ethics and ELSI at a workshop on genome ethics held by the Japan Science and Technology Agency (equivalent to the National Science Foundation in the US) in Tokyo, Japan.

At this workshop, we could not conclude whether chromosome-free technology can lower the existing regulatory hurdles or how it can be implemented in society in the current situation where regulations still need to catch up with the latest technologies. However, we shared the importance of spreading insights into synthetic biology and new technologies to the general public and a sense of urgency that no organization in Japan has been able to do. This was an opportunity for us to work hard on our Education activities.

The press release of the discussion can be found here:

JST-RISTEX「ゲノム倫理」研究会 ケーススタディ 2023　末次プロジェクト第1回ワークショップ（WS）開催レポート - RISTEX 社会技術研究開発センター

3-6. Mr. Kyohei Goto

▶ Discussions with local council members helped us develop the activities necessary for social implementation from a broader perspective.

In addition to issues related to our team’s project, we discussed with Mr. Kyohei Goto, a member of the Suita City Council, to consult with a broader range of stakeholders. We discussed what the local government can do to reduce the number of depression patients and whether people’s attitudes will change if the local government promotes the safety of genetically modified organisms and their products. We thought that if local governments, which have the trust of many people, raise awareness about the safety of genetically modified organisms and their products, people’s understanding of genetic engineering would deepen, leading to social acceptance and the development of new technologies.

3-7. Ms. Miyuki Shiomi

▶Discussions with local council members helped us develop the activities necessary for social implementation from a broader perspective.

We discussed this with Ms. Miyuki Shiomi, also a member of the Suita City Council. Our discussion covered the potential actions that local governments can take to raise awareness of depression, the current and future support and strategies they can provide to those struggling with depression, and the steps that could be taken to mitigate both depression and prejudice against genetically modified organisms. In Japan, factors such as long working hours, limited personal and social time, constant competition, and a test-driven education system that divides individuals into superior and inferior groups can lead to depression. The support offered by local governments to those suffering from depression is not widely recognized. Efforts to reduce depression include solving social problems, educating people about depression support in public institutions, developing educational media that are easy to see and pick up, and increasing the number of self-help groups where people can interact with others with the same depression.

3-8. Kadokawa Dwango Educational Insititute

▶ Discussions with our research colleagues helped us to implement a multi-faceted and imaginative project

We have been part of the N/S High School’s “Kenkyubu” since the team was founded, and the current squad has regularly mentored us. We objectively reviewed our research progress with our advisors to determine what we would and would not do in the future to make the project feasible and created a timeline to accomplish this. Here, we learned the importance of focusing on bioinformatics, narrowing it down to proteins and genes, and minimizing the number of experiments required as much as possible. In March and August 2023, we presented the results of our research and received questions and advice from perspectives not available to the other members, which gave us new views on our project. We were able to gain new perspectives on the project.

3-9. Japan Meetups

The iGEM Japan Community consists of iGEM teams from high schools and universities across Japan and their alums. Two meetups were held this year, the first online meetup in March and the second in person at the Tokyo Institute of Technology in August.

At the meetup in late March, each team presented their project plans and progress and received feedback. At the social event afterward, people from each team were divided into groups. We discussed project-related topics such as Education and Human Practice and non-project-related problems such as team management and fundraising. The exchange of information helped to improve the quality of subsequent activities. The meetup was a great opportunity to share information and enhance the quality of our actions.

At the meetup in late August, each team presented their project for five minutes, followed by a Q&A session. Since many teams had different approaches to their projects, we received much effective feedback during the Q&A session. During the following networking session, we could share our team’s progress and future activity plans with other teams that had participated in iGEM in the past, which was very helpful for us as first-time participants. The sharing session that followed was a significant time for us first-timers, as we were able to share our team’s progress and plans for the future.

3-10. Japanese Society For Cell Synthesis Research 16.0

▶ We presented our project at a conference to get feedback from leading synthetic biologists on the technical aspects of our project for social implementation.

We presented our project results at the “Japanese Society For Cell Synthesis Research” 16.0 conference held at the University of Tokyo to get feedback from a wider audience. Here, we received a lot of advice on our experiments from synthetic biologists who made us aware of many of our blind spots. Based on our feedback, our team reflected on it and applied it to our project.