Difference between revisions of "Team:SDSZ-China/Project"

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                     <li><a href="#Background">Background</a></li>
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                     <li><a href="#Professional">Professional Help</a></li>
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                     <li><a href="#Purpose">Purpose</a></li>
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                     <ul>
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                     <li><a href="#Overview">Overview of the project</a></li>
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                        <li><a href="#Companies">Contact with Local Pharmaceutical Companies</a></li>
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                     <li><a href="#Goal">Our goal</a></li>
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                        <li><a href="#Scientists">Contact with scientists regarding specific technological issues/ suggestions</a></li>
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                    </ul>
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                     <li><a href="#Outreach">Outreach</a></li>
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                     <ul>
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                        <li><a href="#Patients">Contact with Local Hospital and Patients</a></li>
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                        <li><a href="#Centre">Contact with Chengdu Bear Rescue Centre</a></li>
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                    </ul>
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                    <li><a href="#Survey">Survey</a></li>
 
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                     <h2 id='Background'>Background</h2>
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                    <h1 id="Professional">Professional Help</h1>
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                     <p>Bear bile, one of the most famous animal drugs in Traditional Chinese Medicine (TCM), has been
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                     <h2 id="Companies">Contact with Local Pharmaceutical Companies</h2>
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                         recorded in ancient Chinese medicine book as a significant method to treat hepatic and biliary
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                     <p>In order to get a clearer picture of UDCA-contained drug’s manufacturing circumstance in China,
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                         disorders. UDCA, the effective ingredient of bear bile.Aside from the traditional use of bear
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                         our team visited Tianjin Pacific Chemical & Pharmaceutical Company to interview the experts
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                         bile in Chinese medicine, UDCA(ursodeoxycholic acid), the effective ingredient of bear bile
+
                         about current chemical producing methods. According to Mr. Xing Ruwen and Mr. Li Jinlong, the
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                         acid, has a much larger pharmaceutical application. As well as the usage of UDCA in dissolving
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                         most popular method of producing UDCA-contained medicine in the market mainly focuses on
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                         gallstone, its efficacy in primary biliary cirrhosis and primary sclerosing cholangitis (PSC) as
+
                         chemical pharmaceutical procedures. Yet this approach has disadvantages including relatively
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                        an adjunct to medical therapy has been well established. Newer indications include its use in
+
                         weak efficacy and potential harm to health of the workers. He praises our aim to produce UDCA
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                         the management of chronic hepatitis, cirrhosis, post liver transplant rejection,
+
                         medic in biopharmaceutical procedure and consider it very promising. Furthermore, he encouraged
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                        graft-versus-host disease and acute viral hepatitis, where it not only relieves symptoms of
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                         us to cut off cost so that our method can be accepted by the market and the patients. This
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                        cholestasis but also arrests ongoing hepatocyte necrosis. However, the increasing demand for
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                         suggestion helped us to clarify our future goal.</p>
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                         bear bile has caused bears to be in an endangered state: bear poaching and illegal animal trade
+
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                        have greatly dwindled the number of the wild Asiatic black bear. Apart from that, bear bile
+
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                         farming industry in Asia extracts bile through “milking” from the bears, which is operated
+
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                        through surgically implanting a permanent catheter in the animal's gallbladder to obtain the
+
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                        drips. It is unquestionable that the bear bile farming process will lead to both physical and
+
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                        psychological damage in bears. </p>
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                    <h3>Mr. Xing Ruwen</h3>
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                    <p>Mr. Xing Ruwen is the chief engineer in Tianjin Pacific Chemical & Pharmaceutical Company. He is
 +
                        an experienced manager who has been working on Chemical method of producing UDCA-contained drugs
 +
                        for years.</p>
 +
                </div>
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                    <img src="https://static.igem.org/mediawiki/2016/0/04/T--TAS_Taipei--Trip1.png">
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                     <h2 id='Purpose'>Purpose</h2>
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                     <p>Mr. Xing introduces us the traditional chemical procedure to manufacture the UDCA-contained drug.
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                     <p>To find substitute or alternative for bear bile farming, our team will be working on the
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                        Also, he leads us to visit the processing workshop and teaches us many valuable knowledge about
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                         biological synthesis of the main effective component of this important medicine,
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                        drug production. </p>
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                         UDCA(Ursodeoxycholic Acid). This biological approach will not only be more efficient but also be
+
                     <p>According to his opinion, chemical method of producing UDCA-contained drug basically has two
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                         cheaper than the original chemical approach, which is widely used in the current UDCA synthesis
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                         disadvantages: the first one is its high risk; the second one is related to profit, a factor
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                         industry. </p>
+
                         that influences manufacturing the most. For its potential high risk, Mr. Xing conveys that it
 +
                         comes from the utilization of metal sodium. Sodium is well-known for its highly-reactiveness; it
 +
                        is able react violently with water, which at the same time release large amount of heat and
 +
                         might cause potential safety issue to the workers. He praises our thought of avoiding the
 +
                        dangerousness and very much acknowledges our method. </p>
 
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                    <img src="https://static.igem.org/mediawiki/2016/0/04/T--TAS_Taipei--Trip1.png">
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                </figure>
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                    <h3>Mr. Li Jinlong</h3>
 +
                    <p>Mr. Li Jinlong works as the production manager and he also participating in marketing
 +
                        department’s work in Tianjin Pacific Chemical & Pharmaceutical Company.</p>
 +
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                    <h2 id='Overview'>Overview of the project</h2>
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                     <p>Mr. Li patiently answers our questions related to marketing. Analyzing its cost, demand and also
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                     <p>We found that it is possible to convert the main component of poultry bile, CDCA(Chenodeoxycholic
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                         profit, Mr. Li helps us to determined our minds on trying to solve the problem step by step. He
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                         Acid), into UDCA, by employing two enzyme-catalyzed the reactions. First, two enzymes was
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                         informs that currently the successful UDCA synthesis rate is not hight enough and requires
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                        employed to manage the transformation of CDCA to 7oxo-LCA. In the present of
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                         repeating measures to increase its purification ratio. It is very important for us to consider
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                        7a-HSD(7alpha-hydroxysteroid dehydrogenase), CDCA is transformed in to 7oxo-LCA by loosing a
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                         more about the balance between cost and profits if we want to further develop our method. Now,
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                         pair of hydrogen(2H+ and 2e-), the pair of hydrogen is added to NAD+, the cofactor and the
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                         the exported UDCA drugs are highly demanded and we need to find ways to help simplify the
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                         acceptor. The NAD+ is transformed into NADH during the reaction. To regenerate the NAD+ and
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                         production process and to increase the supply of UDCA-contained drugs.</p>
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                        recycle the reaction, to , the LDH(Lactate dehydrogenase) works on pyruvate and take the pair of
+
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                         hydrogen from NADH and transform the pyruvate to lactate and NADH to NAD+.</p>
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                    <p>In the second step, the 7oxo-LCA is transformed to UDCA by 7β-HSDH(7beta-hydroxysteroid
+
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                         dehydrogenase)and GDH(glutamate dehydrogenase).The 7β-HSDH works on 7oxo-LCA and take a pair of
+
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                        hydrogen from NADPH(the cofactor for the second step)and add it to 7oxo-LCA and form a beta
+
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                         position 7-hydroxyl group, which is our target product UDCA. The GDH works on glucose and take a
+
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                        pair of hydrogen from it and add it to the NADP+, to form NADPH to manage the regeneration of
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                        cofactor NADPH for the second step.</p>
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                     <h2 id='Goal'>Our goal</h2>
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                     <h3>Interview</h3>
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                     <p>Our mission is to expression of the four enzymes 7α-HSDH (from ecoli DH5a), 7β-HSDH (from
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                     <p>Q：We still have some questions regarding to the market. It would be such a pleasure if you can
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                         Ruminococcus Torques), GDH (from Bacillus subtilis), and LDH from (Lactobacillus delbruechii
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                        share some of your ideas or understandings about them.</p>
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                         subsp. Bulgaricus)and test their activities. By adding the CBD( cellulose binding
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                    <p>A : Please ask, I’m very glad to help you.</p>
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                         domain)sequnence to the plasmid we construct, we manage to bind our enzyme on gauze. This
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                    <p>Q1: Could you please inform us UDCA medicine’s value in market and its efficacy?</p>
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                         specific design excels in 3 specific ways: first, by controlling the presence of the gauze in
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                    <p>A: UDCA is an cholic acid medicine that has choleretic effect to human bodies. It can cure
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                         the solution, we can control the process of the reaction. Second, when the target enzyme is
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                        various dan diseases like gallstone as well as hepatopathy including hepatic adipose
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                         bound to cellulose we manage to purify the protein we express. Third, the enzyme binding gauze
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                        infiltration. UDCA medicine has stronger healing effect than CDCA medicine while having less
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                         is employed to a machine including the reaction efficiency measuring system and the enzyme
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                        side effects in treatment. However, subtracted from bears, UDCA has a relatively high costs. And
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                         addition controlling system .</p>
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                         using UDCA directly converted by CDCA mainly has two benefits: first of all, it requires a lower
 +
                        cost because CDCA is subtracted from poultry like chickens, ducks, and geese; also, use CDCA
 +
                         instead of UDCA can help protect wild animals (bears.) Also, I consulted experts in our
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                         marketing department about it and they revealed to me that this approach has very high
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                        vendibility that medicines manufactured oversea are in short supply.</p>
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                    <p>Q2: What is the basic principle of this drug design/production?</p>
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                    <p>: First we extract CDCA from the bile of chicken, duck and geese. Then we convert CDCA into UDCA
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                        through two steps of redox reaction. These two substance are isomers than differ in their
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                         three-dimensional structure only.</p>
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                    <p>Q3: We found out that there are only few factories manufactures UDCA medicine. Is it because the
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                        producing process’s complexity? Where is the complexity embodied in specific?</p>
 +
                    <p>A: In fact, the actual process or technology used is not very complex but the key dangerous
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                        factor is the need of sodium, a dangerous, active metal that burns when it meets with water.
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                        Moreover, to consider this issue from other perspectives, UDCA medicine’s production copes wth
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                        the pressure from people’s safety and environment protection concerns. Therefore there are not
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                        too many factories that manufactures UDCA medicine. </p>
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                    <p>Maybe there are only two factories in China that manufactures this active pharmaceutical
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                         ingredient (API) officially; one is in Shenzhen and the other is in Suzhou.</p>
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                    <p>……After biliary drainage, it is very likely that bears will suffer from diseases all over their
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                        body, which is a torture to them. To resolve this problem, researchers and scientists in our
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                        country wish to convert CDCA in order to receive UDCA. Currently, their methods are deeply
 +
                        restrained by the use of sodium due to its danger and difficulty. If you can convert CDCA to
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                        UDCA successfully using enzymes, you are making a huge contribution. </p>
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                    <p>Also, there are a lot of problems in the production of UDCA in medical industry. For instance, we
 +
                        need to consider the safety and profits of this drug. Thus, there are still a lot of aspects
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                        need to be considered and experiments need to be done when involved in industrial
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                        production.</p>
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                    <p>Q: Thank you for your suggestions.</p>
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                    <p>Q4: Could you briefly introduce the issue concerning costs and profits?</p>
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                    <p>A: It is complicated because hydrogen needs to be removed. The chemical composition of UDCA needs
 +
                         to refine repeatedly, which is tricky. For example, a concentration of 70% of UDCA? require
 +
                        three times of refinement at least in order to reach the standard. Also, the raw materials or
 +
                         substances need to be recollected and there will be turnovers and other complex factors during
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                        the process. So the profits is limited. And now the biggest issue is that the danger of
 +
                         production overweights its potential profits.</p>
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                    <h2 id="Scientists">Contact with scientists regarding specific technological issues/ suggestions</h2>
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                </div>
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                <div class="col-sm-6">
 +
                    <h3>Prof. Xu Jianhe</h3>
 +
                    <p>Prof. Xu Jianhe is a well-respected professor in Biocatalyis and Bioprocessing State Key Laboratory of Bioreactor Engineering in East China University of Science and Technology.</p>
 +
                </div>
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                <figure class="col-sm-6">
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                    <br>
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                    <img src="https://static.igem.org/mediawiki/2016/0/04/T--TAS_Taipei--Trip1.png">
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                </figure>
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                <div class="col-sm-12">
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                    <p>With many questions regarding to complex bioprocessing and enzyme catalysis, we write to Prof. Xu, a very famous professor in China and also expert to get further instructions and professional help. At the beginning of our experiment, we decided to employ a two enzyme in one pot catalyzed reaction(see figure.1). However, after our initial attempt, we found out that the reverse reaction was more prevalent than the forward reaction. Thus because of this, the product was actually CDCA, the initial reactant, instead of UDCA, our expected product. This conundrum stopped us from reaching any further into the experiment. At this time, Prof. Xu suggested us to separate the two enzymes into two steps. (see figure 2) After listening to his suggestion, our team worked together and produced our new experiment plan with a two step reaction instead of one. In this way, the end product will not be transformed back into CDCA, and the mass production of USCA proves to be successful. As well as enhancing the biopharmaceutical effect of UDCA, we also aims to reduce the production cost. When we were designing the experiment, we included the usage of cofactors: NADH and NADP+. However, the cost of cofactors can be immense if they are not regenerated. After hearing about our problem, Prof. Xu suggested us finding enzymes to help with the regeneration of cofactors. With his suggestion in mind, we eventually employed GDH(Glutamate Dehydrogenase) to regenerate the cofactor NADP+, and LDH(Lactate Dehydrogenase) to regenerate the cofactor NADH. Carefully answering our questions and giving us other valuable information and cases about our topic, Prof. Xu used his actions to encourage us in refining our experiment and to give it a try.</p>
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                    <h1 id="Outreach">Outreach</h1>
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                    <h2 id="Patients">Contact with Local Hospital and Patients</h2>
 +
                    <p>In addition, we contact local patients from Xuanwu hospital who suffered from liver cirrhosis to
 +
                        discuss the curing effects and prices of various UDCA-contained medicines in the market to
 +
                        determine our direction. Through our interviews, we understood that current UDCA medicines in
 +
                        the market are unaffordable for patients with average or below average income in long term
 +
                        treatment. Also, medicine which price can be accepted by the patients has relatively weak curing
 +
                        effect. In order to solve this problem, we consulted experts from doctors from Xuanwu Hospital.
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                        She reported that UDCA has a large pharmaceutical application. As well as UDCA’s usage in
 +
                        dissolving gallstone, its efficacy in primary biliary cirrhosis and primary sclerosing
 +
                        cholangitis (PSC) as an adjunct to medical therapy has been well established. Newer indications
 +
                        include its use in the management of chronic hepatitis, cirrhosis, post liver transplant
 +
                        rejection, graft-versus-host disease and acute viral hepatitis, where it not only relieves
 +
                        symptoms of cholestasis but also arrests ongoing hepatocyte necrosis.</p>
 +
                    <h3>Patients interview</h3>
 +
                    <p>Q：Hi, how are you Mrs. Zhou?</p>
 +
                    <p>A: Good, good. I’m feeling much better now.</p>
 +
                    <p>Q: If it’s possible, can you briefly explain to us what exactly are you suffering from?</p>
 +
                    <p>A: Ahh. It’s not a problem. Well, I’ve been diagnosed with liver cirrhosis for several years now.
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                        And I’ve been constantly taking medicine to treat it. It costs a lot of money. Too
 +
                        expensive!</p>
 +
                    <p>Q: What is this medicine that you are taking now that is this expensive?</p>
 +
                    <p>A: I don’t really know the exact name, but you can have a look at it. It’s a medicine produced in
 +
                        America.</p>
 +
                    <p>Q: Oh? America? Why aren’t you taking any of the medicine produced locally.</p>
 +
                    <p>A: That’s a long story to tell. This medicine I’m taking is supposed to be composed of UDCA. From
 +
                        what the doctors told me, this medicine is designed to treat diseases like what I have here. But
 +
                        it seems like only the America version works on my. The locally produced version of this
 +
                        medicine is chemically synthesized so I guess it’s not really a good thing. And I can feel it
 +
                        too. Because my stomach often hurts from taking the medicine.</p>
 +
                    <p>Q: Wait… Are you sure of it? Are you sure that your pain comes from taking the chemically
 +
                        synthesized medicine?</p>
 +
                    <p>A: Well yes. The pain usually starts an hour or half after taking the medicine. And the doctors
 +
                        confirmed my theory as well. They say this chemically synthesized version of the medicine would
 +
                        usually have gastrointestinal discomfort as a side effect.</p>
 +
                    <p>Q: Well that’s not good! So have you considered any other choices? Or have the doctors
 +
                        recommended anything else?</p>
 +
                    <p>A: Yes. And that’s actually why I’m telling you how expansive the medicine is. The chemically
 +
                        synthesized version of this medicine is not that expensive. Although it cannot be covered by
 +
                        medical insurance. It’s definitely affordable. The medicine I’m taking now is indeed very good.
 +
                        It doesn’t have any side effects. I guess the only side effects is that it is too expensive. I
 +
                        can’t really afford it now. I really want an alternative. But it sees like the only alternative
 +
                        is bear bile powder.</p>
 +
                    <p>Q: What do you know about bear bile powder?</p>
 +
                    <p>A: I know it’s not extremely expensive so I can probably afford it. But I also know how people
 +
                        acquire bear bile powder. Ugh, I don’t want to cause that much pain to the poor bears. They say
 +
                        no trading, no killing right? So that’s not really an option for me.</p>
 +
                    <p>Q: Yeah. It is indeed very brutal. Well, thanks for your time Mrs. Zhou. We really appreciate
 +
                        your help.</p>
 +
                    <p>A: No problem! Have a good day.</p>
 +
                    <p>Q: You too.</p>
 +
 +
                </div>
 +
 +
                <br>
 +
                <br>
 +
            </div>
 +
 +
 +
            <br>
 +
            <br>
 +
 +
            <div class="row">
 +
                <div class="col-sm-12">
 +
                    <h2 id="Centre">Contact with Chengdu Bear Rescue Centre</h2>
 +
                </div>
 +
                <figure class="col-sm-6">
 +
                    <br>
 +
                    <img src="https://static.igem.org/mediawiki/2016/0/04/T--TAS_Taipei--Trip1.png">
 +
                </figure>
 +
                <div class="col-sm-6">
 +
                    <p>To find out more about the bear bile industry and the protective measures against illegal
 +
                        hunting, our team, SDSZ-China, went all the way down south to Sichuan province, where the
 +
                        biggest Asiatic Black Bear rescue centre is located. There, after exchanging conversations with
 +
                        the staff, we found out that Asiatic Black Bear is listed as endangered on the IUCN red list,
 +
                        and the most efficient way to rescue bears now is buying bile bears from bear farms. (Since bear
 +
                        farming is a legal activity in China, there’s no way to officially put a halt on this). After
 +
                        this trip, we went a bit west and visited a real bear farm where bile is siphoned. There, we
 +
                        learned the heartbreaking fact that people harvest bear bile only to make traditional Chinese
 +
                        medicine. Yet as most of the modern world would possibly agree, traditional Chinese medicine
 +
                        hasn’t prove to have a distinct efficacy in treating diseases, rather it serves as a method to
 +
                        nourish and build up people’s health conditions. Because of the all the above, the need for an
 +
                        alternative way to produce UDCA struck us as extremely urgent. </p>
 +
                </div>
 +
            </div>
 +
 +
            <div class="row">
 +
                <div class="col-sm-12">
 +
                    <h1 id="Survey">Survey
 +
                        <small>SDSZ-iGEM-2016 Survey</small>
 +
                    </h1>
 +
                    <br>
 +
                    <p>1. Age</p>
 +
                    <p>请问您的年龄是？</p>
 +
                    <p></p>
 +
                    <p>0-10</p>
 +
                    <p>11-20</p>
 +
                    <p>21-30</p>
 +
                    <p>31-40</p>
 +
                    <p>41-50</p>
 +
                    <p>51-60</p>
 +
                    <p>61-70</p>
 +
                    <br>
 +
                    <p>2. How much do you know about Bear Bile Extracting Technology? </p>
 +
                    <p>您有多了解活熊取胆？</p>
 +
                    <br>
 +
                    <p>Nothing 没有听说过</p>
 +
                    <p>A little bit 只是听说过，没有深入了解</p>
 +
                    <p>I know this but not quite 有一定的了解</p>
 +
                    <p>I know this quite well 我对此比较了解</p>
 +
                    <br>
 +
                    <p>3. Have you ever known anyone who has or had hepatic or biliary disorders? e.g. hepatitis,
 +
                        fibrosis, and cirrhosis 您是否认识患有或曾患肝胆相关疾病的人？例如：肝炎，肝硬化等</p>
 +
                    <br>
 +
                    <p>Yes 有</p>
 +
                    <p>No 没有</p>
 +
                    <br>
 +
                    <p>4. If the previous answer is “yes”, what’s the patient’s general drug treatment?</p>
 +
                    <p>如果有，您认识的患者一般使用的是哪类药物？</p>
 +
                    <br>
 +
                    <p>Bear bile related drugs (UDCA contained)熊胆相关药物 (含UDCA)</p>
 +
                    <p>Non-bear bile related drugs 非熊胆相关药物</p>
 +
                    <br>
 +
                    <p>5. If the previous answer is “Bear bile related drugs”, what’s the patient’s preference on the
 +
                        type of drugs listed?</p>
 +
                    <p>如果使用的是熊胆相关药物，请问您认识的患者倾向于购买以下哪种？</p>
 +
                    <br>
 +
                    <p>Imported Drug 进口药 </p>
 +
                    <p>Domestic Drug 国产药</p>
 +
                    <br>
 +
                    <p>6. If you don’t know anyone who has or had hepatic or biliary disorders or the person you know
 +
                        does not use UDCA drugs, then what’s your personal preference on the type of drugs listed?</p>
 +
                    <p>如果您不认识患有肝胆相关疾病的人或您认识的患者不使用熊胆相关药物，请问您个人倾向于在购买药物时选择以下哪种？</p>
 +
                    <br>
 +
                    <p>Imported Drug 进口药</p>
 +
                    <p>Domestic Drug 国产药</p>
 +
                    <br>
 +
                    <p>7. Please fill in the answers according to your personal experience/thoughts</p>
 +
                    <p>请您按照情况填写</p>
 +
                    <br>
 +
                    <p>I chose the imported drug, because </p>
 +
                    <p>我选择进口药，因为</p>
 +
                    <p>
 +
                        <strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong>___
 +
                    </p>
 +
                    <p>
 +
                        <strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong>___
 +
                    </p>
 +
                    <br>
 +
                    <p>I chose the domestic drug, because</p>
 +
                    <p>我选择国产药，因为</p>
 +
                    <br>
 +
                    <p>
 +
                        <strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong></strong>
 +
                    </p>
 +
                    <p>
 +
                        <strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong></strong>
 +
                    </p>
 +
                    <br>
 +
                    <p>8. Are you comfortable using/consuming products produced from genetically modified organisms?
 +
                        Check all categories that apply.</p>
 +
                    <p>您愿意使用基因改造的产品吗？</p>
 +
                    <br>
 +
                    <p>Food 食物</p>
 +
                    <p>Medication 藥物</p>
 +
                    <p>Other 其他</p>
 +
                    <p>Not comfortable with using any GMO products 都不愿意</p>
 +
                    <br>
 +
                    <p>9. How does the price of treatment affect your choice? To what extent will your choice be
 +
                        influenced by it?</p>
 +
                    <p>治疗的价格会在什么程度上影响您的选择？</p>
 +
                    <br>
 +
                    <p>Very likely(to affect) 很大程度</p>
 +
                    <p>Moderate level 中等程度</p>
 +
                    <p>Not likely 很小程度</p>
 +
                    <p>Depends (please write down your explanation to the choice)</p>
 +
                    <p>
 +
                        <strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong>__</strong><strong></strong>
 +
                    </p>
 +
                    <br>
 +
                    <p>10. Are you willing to purchase UDCA contained drug that substitutes the conventional Bear bile
 +
                        extracting technology? </p>
 +
                    <p>如果有能够替代活熊取胆的药物，您是否愿意购买？</p>
 +
                    <br>
 +
                    <p>Yes 愿意</p>
 +
                    <p>No 不愿意</p>
 +
 +
                </div>
 +
            </div>
 +
 
             <br>
 
             <br>
 
             <br>
 
             <br>

Revision as of 12:30, 1 November 2017


Project

Professional Help

Contact with Local Pharmaceutical Companies

In order to get a clearer picture of UDCA-contained drug’s manufacturing circumstance in China, our team visited Tianjin Pacific Chemical & Pharmaceutical Company to interview the experts about current chemical producing methods. According to Mr. Xing Ruwen and Mr. Li Jinlong, the most popular method of producing UDCA-contained medicine in the market mainly focuses on chemical pharmaceutical procedures. Yet this approach has disadvantages including relatively weak efficacy and potential harm to health of the workers. He praises our aim to produce UDCA medic in biopharmaceutical procedure and consider it very promising. Furthermore, he encouraged us to cut off cost so that our method can be accepted by the market and the patients. This suggestion helped us to clarify our future goal.





Mr. Xing Ruwen

Mr. Xing Ruwen is the chief engineer in Tianjin Pacific Chemical & Pharmaceutical Company. He is an experienced manager who has been working on Chemical method of producing UDCA-contained drugs for years.


Mr. Xing introduces us the traditional chemical procedure to manufacture the UDCA-contained drug. Also, he leads us to visit the processing workshop and teaches us many valuable knowledge about drug production.

According to his opinion, chemical method of producing UDCA-contained drug basically has two disadvantages: the first one is its high risk; the second one is related to profit, a factor that influences manufacturing the most. For its potential high risk, Mr. Xing conveys that it comes from the utilization of metal sodium. Sodium is well-known for its highly-reactiveness; it is able react violently with water, which at the same time release large amount of heat and might cause potential safety issue to the workers. He praises our thought of avoiding the dangerousness and very much acknowledges our method.




Mr. Li Jinlong

Mr. Li Jinlong works as the production manager and he also participating in marketing department’s work in Tianjin Pacific Chemical & Pharmaceutical Company.

Mr. Li patiently answers our questions related to marketing. Analyzing its cost, demand and also profit, Mr. Li helps us to determined our minds on trying to solve the problem step by step. He informs that currently the successful UDCA synthesis rate is not hight enough and requires repeating measures to increase its purification ratio. It is very important for us to consider more about the balance between cost and profits if we want to further develop our method. Now, the exported UDCA drugs are highly demanded and we need to find ways to help simplify the production process and to increase the supply of UDCA-contained drugs.



Interview

Q：We still have some questions regarding to the market. It would be such a pleasure if you can share some of your ideas or understandings about them.

A : Please ask, I’m very glad to help you.

Q1: Could you please inform us UDCA medicine’s value in market and its efficacy?

A: UDCA is an cholic acid medicine that has choleretic effect to human bodies. It can cure various dan diseases like gallstone as well as hepatopathy including hepatic adipose infiltration. UDCA medicine has stronger healing effect than CDCA medicine while having less side effects in treatment. However, subtracted from bears, UDCA has a relatively high costs. And using UDCA directly converted by CDCA mainly has two benefits: first of all, it requires a lower cost because CDCA is subtracted from poultry like chickens, ducks, and geese; also, use CDCA instead of UDCA can help protect wild animals (bears.) Also, I consulted experts in our marketing department about it and they revealed to me that this approach has very high vendibility that medicines manufactured oversea are in short supply.

Q2: What is the basic principle of this drug design/production?

: First we extract CDCA from the bile of chicken, duck and geese. Then we convert CDCA into UDCA through two steps of redox reaction. These two substance are isomers than differ in their three-dimensional structure only.

Q3: We found out that there are only few factories manufactures UDCA medicine. Is it because the producing process’s complexity? Where is the complexity embodied in specific?

A: In fact, the actual process or technology used is not very complex but the key dangerous factor is the need of sodium, a dangerous, active metal that burns when it meets with water. Moreover, to consider this issue from other perspectives, UDCA medicine’s production copes wth the pressure from people’s safety and environment protection concerns. Therefore there are not too many factories that manufactures UDCA medicine.

Maybe there are only two factories in China that manufactures this active pharmaceutical ingredient (API) officially; one is in Shenzhen and the other is in Suzhou.

……After biliary drainage, it is very likely that bears will suffer from diseases all over their body, which is a torture to them. To resolve this problem, researchers and scientists in our country wish to convert CDCA in order to receive UDCA. Currently, their methods are deeply restrained by the use of sodium due to its danger and difficulty. If you can convert CDCA to UDCA successfully using enzymes, you are making a huge contribution.

Also, there are a lot of problems in the production of UDCA in medical industry. For instance, we need to consider the safety and profits of this drug. Thus, there are still a lot of aspects need to be considered and experiments need to be done when involved in industrial production.

Q: Thank you for your suggestions.

Q4: Could you briefly introduce the issue concerning costs and profits?

A: It is complicated because hydrogen needs to be removed. The chemical composition of UDCA needs to refine repeatedly, which is tricky. For example, a concentration of 70% of UDCA? require three times of refinement at least in order to reach the standard. Also, the raw materials or substances need to be recollected and there will be turnovers and other complex factors during the process. So the profits is limited. And now the biggest issue is that the danger of production overweights its potential profits.



Contact with scientists regarding specific technological issues/ suggestions

Prof. Xu Jianhe

Prof. Xu Jianhe is a well-respected professor in Biocatalyis and Bioprocessing State Key Laboratory of Bioreactor Engineering in East China University of Science and Technology.


With many questions regarding to complex bioprocessing and enzyme catalysis, we write to Prof. Xu, a very famous professor in China and also expert to get further instructions and professional help. At the beginning of our experiment, we decided to employ a two enzyme in one pot catalyzed reaction(see figure.1). However, after our initial attempt, we found out that the reverse reaction was more prevalent than the forward reaction. Thus because of this, the product was actually CDCA, the initial reactant, instead of UDCA, our expected product. This conundrum stopped us from reaching any further into the experiment. At this time, Prof. Xu suggested us to separate the two enzymes into two steps. (see figure 2) After listening to his suggestion, our team worked together and produced our new experiment plan with a two step reaction instead of one. In this way, the end product will not be transformed back into CDCA, and the mass production of USCA proves to be successful. As well as enhancing the biopharmaceutical effect of UDCA, we also aims to reduce the production cost. When we were designing the experiment, we included the usage of cofactors: NADH and NADP+. However, the cost of cofactors can be immense if they are not regenerated. After hearing about our problem, Prof. Xu suggested us finding enzymes to help with the regeneration of cofactors. With his suggestion in mind, we eventually employed GDH(Glutamate Dehydrogenase) to regenerate the cofactor NADP+, and LDH(Lactate Dehydrogenase) to regenerate the cofactor NADH. Carefully answering our questions and giving us other valuable information and cases about our topic, Prof. Xu used his actions to encourage us in refining our experiment and to give it a try.



Outreach

Contact with Local Hospital and Patients

In addition, we contact local patients from Xuanwu hospital who suffered from liver cirrhosis to discuss the curing effects and prices of various UDCA-contained medicines in the market to determine our direction. Through our interviews, we understood that current UDCA medicines in the market are unaffordable for patients with average or below average income in long term treatment. Also, medicine which price can be accepted by the patients has relatively weak curing effect. In order to solve this problem, we consulted experts from doctors from Xuanwu Hospital. She reported that UDCA has a large pharmaceutical application. As well as UDCA’s usage in dissolving gallstone, its efficacy in primary biliary cirrhosis and primary sclerosing cholangitis (PSC) as an adjunct to medical therapy has been well established. Newer indications include its use in the management of chronic hepatitis, cirrhosis, post liver transplant rejection, graft-versus-host disease and acute viral hepatitis, where it not only relieves symptoms of cholestasis but also arrests ongoing hepatocyte necrosis.

Patients interview

Q：Hi, how are you Mrs. Zhou?

A: Good, good. I’m feeling much better now.

Q: If it’s possible, can you briefly explain to us what exactly are you suffering from?

A: Ahh. It’s not a problem. Well, I’ve been diagnosed with liver cirrhosis for several years now. And I’ve been constantly taking medicine to treat it. It costs a lot of money. Too expensive!

Q: What is this medicine that you are taking now that is this expensive?

A: I don’t really know the exact name, but you can have a look at it. It’s a medicine produced in America.

Q: Oh? America? Why aren’t you taking any of the medicine produced locally.

A: That’s a long story to tell. This medicine I’m taking is supposed to be composed of UDCA. From what the doctors told me, this medicine is designed to treat diseases like what I have here. But it seems like only the America version works on my. The locally produced version of this medicine is chemically synthesized so I guess it’s not really a good thing. And I can feel it too. Because my stomach often hurts from taking the medicine.

Q: Wait… Are you sure of it? Are you sure that your pain comes from taking the chemically synthesized medicine?

A: Well yes. The pain usually starts an hour or half after taking the medicine. And the doctors confirmed my theory as well. They say this chemically synthesized version of the medicine would usually have gastrointestinal discomfort as a side effect.

Q: Well that’s not good! So have you considered any other choices? Or have the doctors recommended anything else?

A: Yes. And that’s actually why I’m telling you how expansive the medicine is. The chemically synthesized version of this medicine is not that expensive. Although it cannot be covered by medical insurance. It’s definitely affordable. The medicine I’m taking now is indeed very good. It doesn’t have any side effects. I guess the only side effects is that it is too expensive. I can’t really afford it now. I really want an alternative. But it sees like the only alternative is bear bile powder.

Q: What do you know about bear bile powder?

A: I know it’s not extremely expensive so I can probably afford it. But I also know how people acquire bear bile powder. Ugh, I don’t want to cause that much pain to the poor bears. They say no trading, no killing right? So that’s not really an option for me.

Q: Yeah. It is indeed very brutal. Well, thanks for your time Mrs. Zhou. We really appreciate your help.

A: No problem! Have a good day.

Q: You too.





Contact with Chengdu Bear Rescue Centre


To find out more about the bear bile industry and the protective measures against illegal hunting, our team, SDSZ-China, went all the way down south to Sichuan province, where the biggest Asiatic Black Bear rescue centre is located. There, after exchanging conversations with the staff, we found out that Asiatic Black Bear is listed as endangered on the IUCN red list, and the most efficient way to rescue bears now is buying bile bears from bear farms. (Since bear farming is a legal activity in China, there’s no way to officially put a halt on this). After this trip, we went a bit west and visited a real bear farm where bile is siphoned. There, we learned the heartbreaking fact that people harvest bear bile only to make traditional Chinese medicine. Yet as most of the modern world would possibly agree, traditional Chinese medicine hasn’t prove to have a distinct efficacy in treating diseases, rather it serves as a method to nourish and build up people’s health conditions. Because of the all the above, the need for an alternative way to produce UDCA struck us as extremely urgent.

Survey SDSZ-iGEM-2016 Survey


1. Age

请问您的年龄是？

0-10

11-20

21-30

31-40

41-50

51-60

61-70


2. How much do you know about Bear Bile Extracting Technology?

您有多了解活熊取胆？


Nothing 没有听说过

A little bit 只是听说过，没有深入了解

I know this but not quite 有一定的了解

I know this quite well 我对此比较了解


3. Have you ever known anyone who has or had hepatic or biliary disorders? e.g. hepatitis, fibrosis, and cirrhosis 您是否认识患有或曾患肝胆相关疾病的人？例如：肝炎，肝硬化等


Yes 有

No 没有


4. If the previous answer is “yes”, what’s the patient’s general drug treatment?

如果有，您认识的患者一般使用的是哪类药物？


Bear bile related drugs (UDCA contained)熊胆相关药物 (含UDCA)

Non-bear bile related drugs 非熊胆相关药物


5. If the previous answer is “Bear bile related drugs”, what’s the patient’s preference on the type of drugs listed?

如果使用的是熊胆相关药物，请问您认识的患者倾向于购买以下哪种？


Imported Drug 进口药

Domestic Drug 国产药


6. If you don’t know anyone who has or had hepatic or biliary disorders or the person you know does not use UDCA drugs, then what’s your personal preference on the type of drugs listed?

如果您不认识患有肝胆相关疾病的人或您认识的患者不使用熊胆相关药物，请问您个人倾向于在购买药物时选择以下哪种？


Imported Drug 进口药

Domestic Drug 国产药


7. Please fill in the answers according to your personal experience/thoughts

请您按照情况填写


I chose the imported drug, because

我选择进口药，因为

___________________

___________________


I chose the domestic drug, because

我选择国产药，因为


________________

________________


8. Are you comfortable using/consuming products produced from genetically modified organisms? Check all categories that apply.

您愿意使用基因改造的产品吗？


Food 食物

Medication 藥物

Other 其他

Not comfortable with using any GMO products 都不愿意


9. How does the price of treatment affect your choice? To what extent will your choice be influenced by it?

治疗的价格会在什么程度上影响您的选择？


Very likely(to affect) 很大程度

Moderate level 中等程度

Not likely 很小程度

Depends (please write down your explanation to the choice)

________________


10. Are you willing to purchase UDCA contained drug that substitutes the conventional Bear bile extracting technology?

如果有能够替代活熊取胆的药物，您是否愿意购买？


Yes 愿意

No 不愿意