Organ transplantation is the medical procedure that transplants an organ from donors to recipients in order to replace a damaged or missing organ. It is widely applied to cure various serious diseases including uremia, congenital heart disease (CHD), and end-stage liver disease (ESLD). To promote the development of organ transplantation, our group aims to produce the immunosuppressive drug, rapamycin with a higher production rate at a lower cost.
In order to produce rapamycin that assists organ transplantation through biosynthesis, a thorough background research is required. Thus, our group interviewed several experts to have a better understanding of what technique we should adopt and how we should handle the market competition. During the interviews, suggestions and insights from the interviewees were also noted by the group members. After we finalized our production plan, a social survey regarding public opinion on organ transplantation was also conducted.
Professor Han, Wuhan Polytechnic University; Ph.D., University of Lübeck, Germany, with many years of experience in coronavirus research.
Snapshot of the online interview with Prof. Han
Before designing the implementation plan, our group wanted to have a more comprehensive view of the immunosuppressant industry so that we could decide what method could be applied to our project. Hence, we interviewed Prof. Han, a well-known professor specializing in immunosuppressant research, for more insights.
As was said by Prof. Han, the gap between domestic research and foreign research on immunosuppressants was relatively narrow. However, the capability of developing immunosuppressive drugs in domestic medical companies was significantly lower than companies in foreign countries, which highly affected the domestic medical care industry. Hence, our product as an innovative immunosuppressive drug is vital.
We also knew that immunosuppressants, with a high volume of sales, are commonly used in all forms of treatment from the interview. One of the immunosuppressants related to organ transplantation, cyclosporine, has been put into clinical use since the very early stage. However, according to Prof. Han, with more integrated research, scientists find that rapamycin is far more effective in suppressing it. Therefore, rapamycin gradually replaces cyclosporine and now rapamycin retains its own unique place in the market, which is why we chose rapamycin rather than other immunosuppressants as the main focus of our project.
He also pointed out that the synthesis process of streptomyces rapamycin was complex, requiring multiple genes to act in conjunction with each other, so there were many factors to consider when performing the experiments. He affirmed that the homologous recombination method we proposed for the pre-test was a relatively simple and successful way to increase the productivity of the final product by knocking out unfavorable genes that limited the rate of synthesis. Prof. Han also recommended the idea of establishing a cell factory for the production of rapamycin, like yeast which is commonly used for cell factories, which was adopted in our future experimental design and business plan.
Dr. Wang, Institute of Organic Chemistry, Chinese Academy of Sciences; Familiar with the synthesis process of macrolides and common drugs.
Snapshot of the online interview with Dr. Wang
After interviewing Prof. Han, a cell factory by gene editing as the main production method in our project was agreed upon among the group members. Thus, we interviewed Dr. Wang to have a better understanding of the production technique of rapamycin in nowadays so that our group can improve the method we propose. The interview also aimed to investigate whether the method we proposed is better than the methods currently applied in the immunosuppressant industry.
According to Dr. Wang, the widely adopted methods were metabolic synthesis and organic synthesis of rapamycin. Metabolic synthetic rapamycin by streptomyces rapamycincus could be obtained through purification after fermentation, but it should be noted that the production rate of this method was relatively low. Organic synthesis of rapamycin was not quite feasible either, due to the complexity of the rapamycin molecular formula and the high difficulty of the rapamycin synthesis pathway. He confirmed that by saving the cost of manpower and medical resources, optimizing the biosynthesis pathway would be a better option, which was the method our group proposed.
During the interview, Dr. Wang emphasized production quality of rapamycin must meet the national quality inspection standards. If it is lower than the standards, adverse effects like the impact and difference of radioactive substances on patients would be caused which is quite dangerous. To ensure the safety issue of the product, biological experiments such as tests on mice were planned to be carried out in the future (but we will not conduct any animal experiments during the iGEM project). Experiments on animals were used to rule out late negative effects. There might be splashes of genes and proteins during the experiment, which might affect the animals through the digestive system.
In conclusion, the interview with Dr. Wang ensured that biosynthesis pathway modified by gene editing as an innovative production method of rapamycin is feasible. Insights on production quality and biological pre-test could also be drawn from the interview.
Aside from interviews with experts in the advanced technical research fields, our group also wanted to get some empirical advice on business plans. Therefore, our group interviewed Mr. Ye, who is the product head of a startup pharmaceutical enterprise.
Mr. Ye, graduated from the Department of Pharmaceutical Engineering of Wuhan University of Technology, worked for Shanghai Fosun Pharmaceutical Group, and is currently working as the head of the product in an innovative listed pharmaceutical company in Guangzhou. Freeze-dried preparations, liquid preparations, Chinese medicine extraction and APIs, etc.
Snapshot of the online interview with Mr. Ye
Questions regarding the immunosuppressant market and regulations were raised during the interview. Our main concern was about rapamycin industrialization and cooperation with biopharmaceutical companies, seeking some suggestions to revise our business plan.
Mr. Ye mentioned that the drug efficacy of our product should be competitive with major foreign medicines that were perceived as having similar clinical functions in the context of fair competition. Taking his suggestions into consideration, in the following days we investigated the pharmaceutical market for immunosuppressive drugs and discovered that Pfizer accounted for the majority of the market share. Thus, in our business plan, Pfizer was positioned as the main competitor, and a comparative analysis was conducted in terms of product efficacy and safety.
In order to improve and finalize our business plan, we also asked about the major challenges of biometric technology industrialization during the interview. According to Mr. Ye, there were two major obstacles, i.e., the bioequivalence test and the governmental audit. A bioequivalence test was conducted to test the overall performance and efficacy of the drug, which was also called B1. To address this challenge, we planned to cooperate with local hospitals and medical companies for a pre-test. Through corporation with the hospitals, the doctors and professionals may apply our product for clinical use, which may bring more public exposure as a way of promotion. Meanwhile, the governmental audit was held to give a warrant for the product or comments regarding the reasons for declining the request for entering the market.
We also wanted to investigate the market preference on the way that drugs are given, such as by mouth, injection, and inhalation. As was said by Mr. Ye, there were two ways to use immunosuppressants, which were capsules and oral solutions. Foreign patients preferred oral administration because they think it was relatively safe. However, some components of oral medicine would be metabolized after gastric digestion and the relative efficacy was not high. Thus, in the Chinese market, people generally rather adopted injections for it would be fully absorbed and take effect faster. At present, the majority of immunosuppressive drugs were in the formation of tablets and capsules. Based on the suggestions from experts and market research, we planned to develop injectable drugs.
Finally, we asked about the policy support or restrictions for immunosuppressants. According to Mr. Ye, the central government and local governments issued corresponding regulations on the new medicine or generic medicine and they provided high subsidies to the company. For example, in Shanghai, the sum of the state subsidies and the local subsidies could cover 40% - 60% of the production cost. It could be concluded that China supports the manufacture of a new medicine with considerable financial support. On the contrary, the restrictions on the manufacture of new medicine were newly introduced, which needed to be reviewed by B1, clinics, and the government. As for the immunosuppressants we have made, we assumed that the advantages outweigh the disadvantages in terms of governmental policies.
To have a better understanding of the public opinion on organ transplantation and immunosuppressive drugs, a social survey with 242 respondents was conducted online through snowball sampling in July 2022. To ensure the representativeness of samples, we attempted to include people of different ages, genders, occupations, and residential areas. Due to the pandemic and lockdown policies in Shanghai, it was the most appropriate and feasible method to be adopted at that time.
Figure 1. Survey result of Q3
As shown in Figure 1, the majority of survey participants do not acquaint patients who undergo organ transplantation accounting for roughly 76.86%. Without physical contact or close relationship with organ transplantation patients, it is hard to imagine they can be familiar with organ transplantation surgery. The conjecture is proven by the data collected through the following questions on Q5 and Q6.
Figure 2. Survey results of Q5 and Q6
In Figure 2, there were more than half of the respondents had no idea about organ transplant procedures and few of them heard of rejection and treatment of organ transplantation. Per previous analysis, people have difficulties obtaining information or knowledge about organ transplants if they or their surroundings had related experiences. In general, it can be concluded that the general knowledge of the public on organ transplantation is relatively inadequate. This result pointed out the necessity of our outreach to the public. Thus, to promote our immunosuppressive product and gene knockout technique, it is important to introduce and illustrate the concepts of organ transplantation and immunosuppressive drug to the public first in communication and education activities.
However, organ transplantation is a broad topic with a considerable number of complicated issues. In view of the time constraints of the follow-up science polarization activities, the introduction of organ transplantation needs to narrow down to specific aspects. Thus, the following question is designed to understand whether the general public is familiar with transplant rejection, immunosuppression, and infectious complication.
Figure 3. Survey result of Q4
According to Figure 3 as a columnar analysis chart, it can be observed that most of the participants are more or less aware of transplant rejection and infectious complications, accounting for around 82.64% and 67.77%, respectively. However, it should be noted that the public awareness of immunosuppression, which is one of the core concepts of our project, is relatively low with less than 50% of the people. Hence, the main focus of the communication and education activities would be immunosuppression.
After collecting the knowledge of the general public on organ transplantation, it is vital to have a comprehensive view of the public preference for immunosuppressive drugs. Participants are inquired regarding their potential concerns on issues like whether the drug is safe, cost-effective, and can be widely adopted.
Figure 4. Survey result of Q7
As shown in Figure 4, the safety of drugs is the aspect that is more concerned by the people than any other aspect for the number of ‘very concerned’ is the highest. Accordingly, safety would be the top priority in drug development and promotion activity. In addition, whether the drug is cost-effective is also widely concerned with 22.73% of people as ‘very concerned’ and 31.82% of people as ‘relatively concerned’. It might result from the fact that most immunosuppressive drugs on the market are expensive for people with an average income level. Thus, our group dedicates to lowering the cost of immunosuppressive drug production so that the price can be set as more affordable. Although the type of medicine, the life cycle, and the universality are not the top concerns, they will be addressed in drug development as well as communication and education activities.
