Difference between revisions of "Team:SHSID/Human Practices"

Solving the shortage problem for tropane alkaloids is essential for meeting the demands of pharmaceutical market. Our team’s goal is to construct a more efficient supply chain for tropane alkaloids, which will lead to low-cost of tropane alkaloid-based medications. To do so, we need to figure out what is the most effective and efficient way of achieving our goal, and how our work will affect people.

We have conducted surveys, community research, and consultations with various people in pharmaceutical fields to identify the most effectual way of meeting our goal. Talking with people in the field, we recognized that we have much to offer to the industry and people. At last, we have obtained the conclusion of genetically modifying the process of tropane alkaloids production.

Our initial research about the topic provided us with a limited scope and knowledge about the industry and market of tropane alkaloid-based medications. From this stage, we started to integrate human practices into implementing our topic.

To truly understand the problem and apply our work to wider audience, we needed answers for our questions we had. Thus, we have conducted surveys to the general public and interviewed people in the pharmaceutical industry. We needed to identify: How big is the market? What is the usage of tropane alkaloids? What is causing the problem? What can we do to solve the problem?

We first needed to identify the problem and its cause in depth, so we conducted research and interviews on the basic principles of producing tropane alkaloids and its usage in pharmaceutical industry.
Tropane alkaloids are widely used in medicines, including anesthetic, acetylcholine inhibitors (mascarine M-receptors), and many other anticholinergic drugs.
Tropane alkaloids are originally extracted from a plant called Solanaceae.
The process of extracting tropane alkaloids is slow and inefficient, not being able to meet the demands of pharmaceutical market.

Having understood multiple facets of the problem, we then conducted online surveys to find out the market size and market demand of tropane alkaloid-based medications.

The online survey provided us with valuable information about the market which gave us guidance through the process of our product design. A majority of the respondents were not aware of the shortage of tropane alkaloid, so we have decided to raise awareness of this issue by communicating with the public. (communication）

Most people use or had used tropane alkaloid medication.
People in need, which means that they depend on, of tropane alkaloid-based medication is not very much.
However, people in need of tropane alkaloid-based medication can feel the shortage of tropane alkaloid medication.
A Majority of the people were positive about producing a genetically modified pathway of producing tropane alkaloid-based medications.

Knowing about the market of tropane alkaloid-based medication, we needed guidance for our solution. In order to do this, we needed guidance from experts in pharmaceutical industry. Thus, we had meetings with alkaloid experts and pharmaceutical company’s CEO to seek opinions on our topic. Our conversation with them focused on how synthetic biology can be utilized to provide answers to the problem and bring values to our society.

After doing market research and having discussions with experts in the field, we have identified stakeholders’ needs and problems that pharmaceutical industry is facing regarding tropane alkaloid-based medications.

Analyzing the problem, we have decided to employ genetic modification as our primary method of producing our final product, which is cell factory. Our plan is to genetically engineer DNA sequence of cell into cell factory which will be able to produce putrescine, a necessary component for tropane alkaloids.

To validate our plan and lab procedures, we have once again met with experts. We have received many positive feedbacks and have modified our plans accordingly.

Dr. Huang has examined the outline of our research project and pointed out some defects. First, he suggested that instead of one single plasmid, we can construct three different plasmids with three different promoters to increase the chance of success of our experiment. Second, he advised that we should use low concentration of yeast cells when amplifying DNA of yeast, because the cell walls of yeast can inhibit the activity of DNA polymerase. Third, he proposed that we directly insert edited-genes into yeast chromosomes, which might increase the production of putrescine. We revised our project accordingly.

Then, we inquired about the functions, shortage, and substitutability of tropane alkaloid-derived medication. Tropane alkaloids are used extensively in the medical field: anesthetics, acetylcholine inhibitor, etc. Traditional methods of producing tropane alkaloids take more than 13 steps and have high cost, but current genetic editing methods cannot effectively increase the efficiency of tropane alkaloid production, hence this implies the importance of our project. Tropane alkaloids are also highly insubstitutable, further proving the importance of our project.

(Before setting up Qinhao Pharmaceutical Company, Dr. Wang obtained his PhD degree from Chinese Academy of Sciences and completed his postdoc research at Zhejiang University)

Dr. Wang has introduced to us the process of research and development for new medicine. Generally the research and development process for one drug costs 28 Billion RMB and 10-15 years globally. New ways of production for drugs would be acceptable, and the two deciding factors for the global implementation of the production method are lowering cost and safety. Even though genetic engineering is currently not necessary, it has a broad application prospect in a wide range of areas.

Wishing to receive more insights on pharmaceutical drug production and its prospects, we visited the transnational pharmaceutical corporation Roche, and interviews its Research and Development Department Head, Dr. Hong Shen. Our interview revolved around two major topics, the procedures of drug production, and the impact & feasibility of our project.

The first stage of drug development is the basic research stage, where researchers specify the target class they want to target, often the pharmacologic or genetic modulation of which leads to an anticipated favorable impact on diseases. After deciding on a target, a researcher would then investigate the biological rationale of the disease, the pathway, and targets that are responsible for certain diseases, so they can select chemical compounds accordingly. From a library of chemical compounds, researchers employ a series of assessments, eventually selecting 2-3 compounds that demonstrate efficacy on the target. The compound is then tested on animals to assess its practical effectiveness. If proven effective, the medicine enters the pre-clinical stage, where the compound is manufactured into pills, tested for toxicity, and employed with a clinical research plan. This stage is the preparation for the clinical-stage, where the newly manufactured pill is distributed to human volunteers to test efficacy, safety, and competitiveness in the market. If a compound fulfills all of the requirements and is proven to be beneficial to both a company and society, it will be mass-produced and distributed to the public.

The predominant reason for the long period and high cost is due to the rigorous requirements of a marketable medicine. A medicine that is considered vendible must be effective, safe, profitable, and specifically targeted at certain causes. Failures are inevitable during the process. Most of the failures occur in the early research stage, where the compounds are either ineffective or unsafe. Though the requirements are not complicated, researchers spend the most time here doing basic research on the biological rationale of disease and proving a compound's function. And in later stages, the market applications of the medicine are yet to be tested. Therefore the development of a new drug of the most rigorous in its early development.

The importance of our project comes in when compound production and medicine manufacturing is needed. Throughout the process of creating a medicine, various types of compounds are needed to be tested, and the eventual medicine also needs to be manufactured to be tested on human subjects. Therefore, increasing the efficiency and yield of synthesizing different compounds is also paramount. By implementing the use of cell factories instead of traditional factories or chemically synthesizing medical compounds, we can reduce the scale of production, making it easier to directly obtain more types of compounds. This is because, by directly "programming" a cell to manufacture certain compounds, the steps of synthesizing compounds are simplified. For instance, in our project, we managed to yield putrescine from yeast cells, this means that when manufacturing certain compounds or medicines, we do not need to first synthesize putrescine, instead, we can directly input the putrescine that is yielded from cells. Also, as such cells are easily cultivated with large numbers in labs, the procedure of synthesizing compounds is much easier and can yield more. All one needs to do is to construct a cell, and wait for its yield in the lab. Therefore, our project, in contrast to the existing means, can reduce the time, simplify the process, and increase the yield of creating and synthesizing certain compounds.

After explaining the procedures of drug development, Dr. Shen explained the prospects of the medical industry. He explains that even though the process of developing drugs remains largely the same, the manufacturing process of medicines can be improved. The trend is shifting towards making manufacturing more efficient and cheap.

As we presented Dr. Shen with our project, he made comments and suggestions on our possible future expeditions and modifications. He pointed out that chemical sythesis of putrescine has been implemented on a large scale, but using cell factory to biologically synthesize putrescine is a new approach that has not been looked into. However, putrescine is only a raw material for chemically synthesizing other various medicines. So Dr. Shen pointed out that as the next step, we can elaborate further on what we have, and modify the cell factory into directly producing tropaine alkaloid based medicinal compounds. That way, we can maximize the advantage of a cell factory being able to directly biologically synthesize pharmaceutical compounds which used to be only chemically synthesized through multiple steps.

Back in 7/1, we have been analyzing the survey that we have constructed and been sending to people to fill out. The survey contained several questions that all relates to one central question--people's awareness of Tropane Alkaloids and the consumption of Tropane Alkaloid products in our community. Through approximately 500 samples, we have been able to roughly analyse the current level of consumption and awareness of Tropane Alkaloid and its products.

Out of all the participants that filled the survey, around 41.81% of the respondents age within the span of 10~20 y/o. Yet as we look at the histogram of the respondent's age that is skewed upwards and bimodal, we can see that people who are rather young have been showing more concern to our survey. The second most abundant age group is of people aged 30~50, which shows their high concern of our project, which is an important element in certain medicine and other related pharmaceutical products. Though no direct causational relationship can be concluded, we can hypothesize this trend as a rising concern of such products within people of a younger age, and the middle-aged have high concern of these products as they could either be using related products, or they have an increasing concern with these products (perhaps due to that of Parkinson's disease or of anaesthetics).

Though a large number of respondents, only a few of them have a high level of need for TA products. As the pie chart presented below shows, it is pretty obvious that the majority said that TA-med is not exactly important in their life. Though most of our respondents responded by saying that TA isn't a necessity in their life, we can still see that nearly a third of the respondents said that they use TA medication or even a daily necessity for them. As we were designing our survey, we expected a smaller share of the population to show some level of importance with TA medication, but unexpectedly there was actually a higher level of need than that of our expectation.

Though not surprised, most of the respondents were unaware of the current shortage in supply that the Tropane Alkaloid market is currently facing. Having a rather large demand due to the various ways in which tropane alkaloids could be chemically manufactured into products that we can use in our daily life. This lack of awareness of shortages in supply is one thing that we should consider, for not being aware means that we would not take action. Speaking of such lack of awareness, it further fortifies the significance of our project to increase awareness of TA products in our lives.

As we can see from the bar graph below, most of the respondents who said that they have sensed a lack of TA products in their life have came to realize such insufficient supply through these occasions, with the increasing difficulty of purchases and increased price being the most abundantly chosen choices. Again, this emphasizes on the importance of further improved techniques on tropane alkaloid production as only with more supply of TA products like atropine would people be able consume these products with more ease. An increased supply of tropane alkaloid and its products could highly resolve problems that our market is currently facing.

After conducting a chi-square test of independence with age/identity and all of the other questions (including the level of need, frequency, awareness of current shortage, etc.), we have come to realize that there is no evidence showing the frequency of usage and the awareness of the current market shortage of TA products are independent of age. Though we cannot assume them to be dependent, we can infer that there is a certain relationship between aging and consumption of TA-related medicines, and the accumulation of knowledge and acknowledging current market situations. Not only did we make the survey focused on Tropane Alkaloids alone, but we also further investigated people's opinion on GMO products, which is to some extent what we have. Turns out that, with a p-value of 0.058, the respondent's identity do have some unknown relationship with their response, which could be one thing that we can further invest in by doing social experiments and fully understand the direct relationship between one's social status and identity and their attitude towards a product of an uprising technology.

Further looking at the other variables that we took into concern as we were designing our survey and analyzing them, the calculated p-value has shown that age and identity had a high level of independence (p<0.001) with their perceived significance of TA, expectations on further technology to modify such products. Such statistical evidence proves to us how age and identity are not influential factors that alter one's perception of these products. Beyond that, we can further infer that the significance of such product is shared equally among every person in our market and that the future of genetically engineered products will face equal pressure, no matter from what sorts of people.