Survey
Ethics
Synthetic biology, as a newly-presented subdiscipline of life sciences, has appealed to lots of researchers devoting themselves to it. As the world has got insights into the information covered by the genes, they’ve mastered their biological functions. It is just like an engineering job that these biobricks are assembled by synthetic biologists to become a biological device, which can complete novel tasks. From the moment it emerged, it moved towards the public accompanied by many controversial topics. A large portion of people stoutly negates the field with the thought that it is as frightening as ‘human cloning’.
At the present, the basic ideas in synthetic biology include two lines. One is to design and construct new biological parts, modules and system. The other is to redesign the existing and natural biosystem. Both ideas are for benefits of human society. Obviously its task is to standardize the gene bioinformation, and manufacture operable standard bioparts. However, it seems at the opposite sides with the biodiversity of the nature. How can we resolve this kind of contradiction? And how do our human beings look upon the numerous social problems it causes such as the patents and impartiality?
The ultimate aim of synthetic biology is to synthesis a completely artificial life, which is notwithstanding fascinated to many of us. Nevertheless, it makes the whole society feel terrified to the unknown vita. In that way, whether or not we should advocate this kind of creativity for life? And how can we evaluate the benefits and risks in synthetic biology? Or how can human beings find a balance point of the double-edged sword?
To find the answers to all the above questions, we’ve conducted a discussion on the ethical issues in synthetic biology with Doctor Xie Guangkuan of the Institute of Medical Humanities of PKU. At the same time, we estimated our project on ethics according to the Four Principles of Bioethics.
The First Principle: BENEFICENCE
Compared with other traditional detection methods, the biggest advantage of the detection of nucleic acid is the great shortened of the time without the decrease of the specificity and sensitivity. And not to mention the influence of time cost on the economy of a gradually developed society, only consider its role in the prevention and cure of tuberculosis is enough to make people wonder. In the diagnosis and treatment of TB, traditional methods, such as bacteriological detection methods, need one to two months to get the result, while in clinical work, no doctors dare to give treatment after such a long time waiting for the result, because the disease may develop rapidly during the waiting time, which may lead to irreversible consequences. Therefore, in the current clinical work in China, treatment would be given first while waiting for the detection result of bacterial culture. This is indeed a way to avoid the development of the disease, but for the misdiagnosis patients, on the one hand, the right treatment has been delayed, on the other hand, the wrong treatment may lead to the resistance to anti-tuberculosis drugs. Nucleic acid detection can effectively avoid these problems, the existing mature detection technology of Mycobacterium tuberculosis usually takes only a few hours to get the result, which can greatly reduce the detection time and is more conducive to the realization of the treatment after diagnosis, which thus can avoid delay treatment and error treatment.
Although nucleic acid detection has much advantage compared to traditional detection method, the detection of nucleic acid is still not able to replace the traditional detection method. The main reason owes to its expensive price. Besides that, the traditional detection method has been developed for many years, and through the traditional detection, the staffs can see mycobacterium tuberculosis directly, which give them more confidence on making a definite diagnosis. Thus as a new method which gives the result through an indirect way, nucleic acid detection method is refused from the idea of part of doctors. And in this paper, we will focus primarily on the former: the advantages and disadvantages of nucleic acid detection in the economic analysis compared with the traditional detection method. Through consulting Beijing research institute for tuberculosis control, we have learned that the current traditional smear technology price is about 15 yuan, and 60 yuan for bacterial culture, that is, the price of traditional detection method is about 100 yuan, and the current method for nucleic acid detection such as Hans needs 525 yuan, X-pert detection technology needs 650 yuan, which means the detection method of nucleic acid is about 5-6 times as much as the price of traditional methods, leading to the conflict psychology for patients to use nucleic acid detection method. In addition, as for the hospital, the cost of traditional detection method is relatively low, while providing nucleic acid detection method, hospitals need to be equipped with more expensive equipment, according to the introduction of the lab director from Beijing research institute for tuberculosis control, the construction of the current nucleic acid detection platform costs tens of thousands or even hundreds of thousands, although most large hospitals have the ability to afford this instrument. However, for small or medium hospitals, it is still difficult to be equipped with such expensive instruments. And dramatically, the incidence of tuberculosis in China in rural areas is much higher than urban areas, which means most of the tuberculosis patients cannot use nucleic acid detection method. Thus no matter from the view of hospital or patient, the use of nucleic acid testing is out of affording, which leads to the limitation of its application.
And our project which is also based on nucleic acid detection has given a clever solution to the problem. We concentrate the detection process in a handy container. The first to avoid the need for nucleic acid detection laboratory platform, which thus can solve the problem for small hospitals to withstand the high cost of laboratory established. On the other hand, our instrument uses a new principle of work and cost much lower compared with the previous nucleic acid detection method.
And our project which is also based on nucleic acid detection has given a clever solution to the problem. We concentrate the detection process in a handy container. The first to avoid the need for nucleic acid detection laboratory platform, which thus can solve the problem for small hospitals to withstand the high cost of laboratory established. On the other hand, our instrument uses a new principle of work and cost much lower compared with the previous nucleic acid detection method.
The Second Principle: EQUITY
Whether in China or in the world, the gap between the rich and the poor, the inequality of regional resources is a problem that we cannot ignore. When the unequal distribution of resources comes to the diagnosis of Mycobacterium tuberculosis, the incidence of tuberculosis is getting worse caused by the delayed diagnosis of tuberculosis in relatively backward regions. We take Beijing research institute for tuberculosis control and the Center for Disease Control of ZhengHe in Fujian Province as the representative of the developed cities and remote mountainous areas, and detailed consultation with the two agencies have been made. As expected, Beijing research institute for tuberculosis control has a variety of innovative nucleic acid testing equipment, although they said these devices are indeed expensive, not often used in clinical, but they have these conditions. And for Center for Disease Control of ZhengHe in Fujian province, it has only the traditional detection facilities, no conditions to build a nucleic acid detection platform. What’s worse, for the region's people, the majority have no economic ability to bear the cost of nucleic acid detection. This has led to the unfairness in the detection of Mycobacterium tuberculosis, and the economic level is the detection means of the watershed.
As stated above, our project is trying to put a set of nucleic acid detection in a small container, in line with the concept of Point-Of-Care, making a detection which is cheap, convenient and simple. Such a set of equipment will be able to minimize the embarrassment brought by the differences in the region. And the relatively backward areas can have the opportunity to use the new methods to reduce the time of the detection of tuberculosis, and improve the detection specificity and sensitivity, even in the absence of qualified laboratory conditions.
The Third Principle: RESPECT
As a country whose incidence of tuberculosis is ranked second in the world, there are lots of TB patients in China. And according to the relevant laws and regulations in China, the TB patients are limited in certain industries such as teachers. In catering and other industries, people are required to have the certificate issued by the hospital to prove they are not the TB patients. If TB detection becomes easier, it is expected that this part of unit can be equipped with such a testing tool for practitioners to verify, and even other industries will hope that their employees are not TB patients, thus they may be equipped with the appropriate testing tools as well. Although doing so is beneficial to the control of tuberculosis, it can also make the patients feel that their privacy is not protected, and they may feel social discrimination and disrespect. For this case, we do not think that it can be the reason for the detection of nucleic acids should be fixed. The state should take other measures, such as the restriction of enterprise or institution to buy such disease detection tools, etc.
CONCLUSION
To sum up, we believe that the project we are working on is in line with the principles of ethics, which will help promote human health, and to some extent improve the imbalance of social medical resources.
Economics
Introduction and project abstracts
The goal of controlling Tuberculosis（TB）is to make as many patients as possible receive treatment without delay, where diagnostic technology is the key. However, global progress in the diagnosis and treatment of TB-MDR is slow. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease, while only less than 25% of patients could be detected in TB-MDR high-burden countries [1]. Given that in China the golden criterion for diagnosis is still sputum smear-positive, the limitation of diagnosis remains. Long detection time and low sensitivity of sputum smear microscopy result in the low detection rate, which is less than 1/3. New technology, refering to nucleic acid detection method, is relatively difficult to be used in rural countries due to its high cost and technically demand. China ranks the second high TB burden country while health resource is scarce and uneven. In this case, looking for a simple, rapid and accurate diagnosis method is urgent, which is also the key to reasonable allocation of TB related health resources.
The project of Peking 2015 iGEM team is making use of junction of dCas9 and target RNA in the CRISPR, which leads to the identification of two specific sequences of mycobacterium tuberculosis. At the same time, two divided fluorescent protein, both of which are connected with dCas9 and mutually close to each other, generate fluorescence and then transfer fluorescence signal through the device. The technology has many advantages. For instance, testing time is relatively short, it is portable and easy to operate. In the meantime, it has high sensitivity and can transfer the invisible nucleic acid into visible signals, which helps high-tech detection of TB can be promoted in remote villages or cities that are densely populated but with poor sanitation.
This report is a feasibility analysis of our project in the entire TB diagnosis market in two aspects. Namely the supply and demand of rapid molecular tests.
Supply in TB diagnosis market
1. The diagnosis method currently used.
(Data sources: Ding Beichuan, Director of Center Lab of Beijing Research Institute for Tuberculosis Control)
2. Competitive situation of the TB detection products
According to the table, high-tech products currently used are similarly utilize nucleic acid detection techniques, including conventional PCR method, real-time fluorescence quantitative PCR, Gene Chip and X-pert. The ratio of using molecular techniques and sputum smear microscopy is 5: 110. Among all the molecular techniques, conventional PCR method, real-time fluorescence quantitative PCR and gene chip total accounting 7/25. Around 18/25 patients chose the X-pert technology. As it indicates, molecular detection products have not been widely used, and in this case, X-pert is the most popular molecular detection techniques. Number of people using molecular detection is far less than people who use sputum smear microscopy. Despite being the golden criterion, sputum smear microscopy has many advantages, such as specificity, low cost and free policy. However, in 2014, about 7,271 TB cases were reported in Beijing, of which only less than 3,000 people are sputum smear positive. Although there are lots of advantages of using sputum smear microscopy, low sensitivity is indeed the serious shortcoming for diagnosing TB.
(Data sources: Company official website )
3. Substitutability of competing technologies
Currently the diagnosis of tuberculosis mainly three kinds: bacteriology, immunology and molecular biology. Bacteriological methods, including sputum smear microscopy, mycobacteria culture and isolation identification, recognize TB directly and identify the species of TB in the meantime. Sputum smear is simple and cheap, but the positive rate is very low, which makes it not an ideal screening tool. Culture is considered the "gold criterion", but considering long time to waiting for mycobacterial growing (solid culture generally costs 4-6 weeks to grow, and fast liquid culture also requires two weeks), it cannot provide patients with accurate information of TB infection in time. Immunology method is fast, simple and easy to operate, but it is an indirect method that detects antibody in serum. Sensitivity and specificity are both relatively low, so WHO has not recommended it as a routine diagnostic method to detect active TB.
As for molecular methods for the direct detection of specific nucleic acid sequence of TB, it is rapid and sensitive, which becomes the current trend of in vitro diagnosis of TB. However, the bottleneck lies in its high requirement on facilities and operator skills. The high cost of reagents is also a major obstacle for promotion. It’s worth noting that our core competitiveness is not only the sensitive, specific and rapid detection just like other molecular detection methods, but also the advantage of portable device that is easy to operate, minimal requirement on staffing levels. Our product is very beneficial in tuberculosis epidemic area, most of which are remote countries and densely populated cities. To promote the use of our product in these areas, it’s essential to meet the needs of diagnosing TB accurately and easily as soon as possible.
4. Prediction of Peking 2015 iGEM project
(1)Cost/RMB
(2)Effect
Demand in TB diagnosis market
1. Consumers.
Target customers of our product are institutes in all levels for TB control and other clinical hospitals for pulmonary, chest and infectious diseases. Besides, it’s especially for hospitals and TB control institutes in county and municipal levels. Due to the lack of resources and funding of grass-roots medical institutes, there are always no professional molecular labs or expensive instruments. Thus, our device can provide advanced molecular detection methods for common people with its simple and quick feature.
2. Prevalence Rate [2].
The government invests 3 million yuan into Beijing Research Institute for TB Control every year, with a total number of 30 million into all of the TB control institutes in Beijing, while there is just 2.5 million yuan disposable for all the TB control institutes in Hebei Province. According to the fifth national tuberculosis epidemiological survey, 2010, three features characterize the epidemic situation of tuberculosis in China. (1) Morbidity in rural areas is significantly higher than that in cities, which are 569 and 307 per 100 thousand people respectively. (2) The problem of regional imbalance is severe in the aspect of the prevalence rate. In the western region, manpower resources for TB control are much deficient because of poverty and remoteness. Therefore, these areas require a diagnostic method that is simple and quick, to reduce the morbidity. (3) It is estimated that there are nearly 5 million active pulmonary tuberculosis patients above 15 years old. This huge number indicates that China indeed needs a reliable and efficient diagnostic method.
3. Considerations when customers purchase.
One factor that clients will certainly consider but is easily ignored by us is the simplicity of the detection toolkit. One method that can be simply operated by lab workers is easy to be popularized. Since 1994, the government began to generalize the molecular detection methods. Unfortunately, due to its complex operation process and high cost, only 2 institutes in Beijing are covered by the molecular detection platform. Although the golden standard for TB diagnosis is still the positive result of bacteria culture, its sensitivity is very low, with only one third of the patients can show positive results. As the great improvement of molecular detection methods, multifunctional and quick devices have appeared, which shows a trend of popularization of these methods. Nevertheless, from the perspective of lab workers, convenience of operation process is very important. Lack of simplicity means the difficulty to generalize this new technique. In conclusion, except for the primary requirements of high sensitivity and specificity, we must take the operational convenience into account.
4.DCF Valuation Method
Based on the data above, we use DCF valuation method to predict the value of our product if it’s put into operation.
(1) Price estimate: compared with the usages and the costs of other similar product we estimate previously, it’s predictable that the price of using our devices and kits once is around 100 yuan. A device is about 200 yuan, which can be utilized repeatedly, and it belongs to the fixed costs.
(2) The first year of sales: According to the data provided by the Beijing Research Institute for Tuberculosis Control: The usage of X-pert a year is about 3600 people, and the usage ratio between molecular detection and sputum smear is 5: 110. Also, the ratio of patients and people who get tested is about 2:15. According to The fifth national tuberculosis epidemiological survey in 2010, there were 4.99 million patients in China, and then consider the budget limitation of other provinces in China except Beijing, the proportion of the usage of molecular detection and sputum smear is far lower than that in Beijing. So it could be estimated that there will be 10 million patients expected to utilize the technology in the whole country and the capacity of molecular detection market is more than 1 billion.
(3) Next 2-5 years sales: According to the report, the active tuberculosis prevalence rate in China is about 459/10 million, and annual decreasing rate is 0.2%. So next 4 years, it is estimated that there will be 9.98 million, 9.96 million, 9.94 million, 9.92 million people use the technology. With the gradual promotion of molecular detection technology, the market will be expanded, so we predict up to 40 million people will use the technology in 4 years, the market capacity will be up to 3 billion yuan.
(4) As capacity of the first sales’ cycle amounts to 4 billion yuan, considering the costs of our product, which is 50 yuan for single use, the cash flow will be approximately 2.5 billion yuan.
Squaring up the discounted parameters (1 / (1 + 0.12) ^n, n = 1,2 ..), the discounted present value of 5 years adds up to 2,018,500,000 yuan.
All in all, what we provide is a portable and accurate nucleic acid detection product that meets the rigid demand in Tuberculosis epidemic area. Future molecular detection market grows fast, and our product will soon have a share of nearly 40% of its volume as expected.
References:
1. WHO. Global Tuberculosis Report 2014[M]. World Health Organization, 2014.
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4. Nienhaus A, Schablon A, Costa J T, et al. Systematic review of cost and cost-effectiveness of different TB-screening strategies[J]. BMC health services research, 2011, 11(1): 247.
5. GONG Y, WU G, LI Y. Cost-effectiveness, cost-utility and cost-benefit analysis of various projects for TB control[J]. Chinese Journal of Hospital Administration, 2001, 12: 000.