Ethics Discussion
Figure 1. The genomic map of the Mycoplasma laboratorium, a chemically synthesized bacterium, also called “Synthia”. The creation of Synthia has triggered heated bioethical discussions on synthetic biology.
Synthetic biology, as a newly developing subdiscipline of life sciences, has appealed to lots of researchers devoting themselves to it. Nowadays, scientists has got great insights into the information provided by genes, so next step they want to master the biological functions of genes. It is just like engineering job that these biobricks are assembled by synthetic biologists to become a biological device, which can complete novel tasks. However, sythetic biology caused many controversial topics as soon as it emerged. A large portion of people stoutly negates it with the point that it is man-made life.
At present, the basic ideas in synthetic biology include two lines. One is to design and build new biological poarts, modules and system. The other is to modify the natural biological systems. However, it seems to go against the law of nature. How can we resolve this kind of contradiction? And how to look upon the numerous social problems it causes such as the patents and impartiality?
The ultimate aim of synthetic biology is to synthesize a completely artificial life, which is notwithstanding fascinated to many of us. Nevertheless, it makes the whole society feel terrified to the unknown area. 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?
To find the answers to questions above, we conducted a discussion on the ethical issues in synthetic biology with Doctor Xie Guangkuan of the Institute of Medical Humanities of PKU. According to Doctor Xie, we estimated our project basing on the Three Principles of Bioethics.
The First Principle: BENEFICENCE
Figure 2. Three of our team members are discussing with Doctor Xie Guangkuan from the Institute of Medical Humanities, Peking University.
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
Figure 3. Doctor XIE Guangkuang led us to think in the way of “Three Principles of Bioethics” during the discussion.
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 consultations 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 to promote human health, and to some extent improve the imbalance of social medical resources.
Economics
Introduction
The overall goal for control of Tuberculosis (TB) is to ensure prompt identification and treatment of infectious patients, and to eliminate TB ultimately. Global progress was seen in last two decades, but not enough to reach the aim of TB control, where detection method is the major limitation
There are various detection methods. Sputum smear microscopy remains the mainstay of TB diagnosis in China and other resource-constrained countries, which is inexpensive but not sensitive particularly in people with HIV and in children, while culture serves as the current reference standard but takes weeks and requires laboratory capacity. Rapid molecular tests to diagnose TB and drug-resistant TB such as Xpert requires expensive equipment and trained laboratory staffs, making it not widely adopted in China. With the low percentage (37%) of new pulmonary cases that were bacteriologically confirmed, China accounted for 11% of the 5.7 million new and relapse cases of TB that were notified in 2013 [1]， which has an urgent need for accurate and rapid detection methods.
Peking iGEM 2015 develops a detection device using the CRISPR/Cas9 system. We have shown that CRISPR/Cas9 systems can be engineered to target specific DNA sequence of Mycobacteria tuberculosis by using a mutant of Cas9 nuclease without double-stranded endonuclease activity (dCas9) and two “guide RNA” with complementarity to specific DNA target site screened by bioinformatics. Fusing dCas9 with split reporter proteins, the signal can be easily read out.
What is the supply and demand in TB testing market? Can our device really be applied to TB diagnosis in China? Is there any possibility that advanced molecular tests will replace traditional methods? Are there other features should our device have? To find the answers to these questions, we’ve conducted a discussion on the economic issues with Mr. Ding Beichuan, Director of Center Lab of Beijing Research Institute for Tuberculosis Control.
Supply in TB testing market
1.The diagnosis method currently used.
Table 1. Comparison of current diagnosis methods in China
(Data sources: Ding Beichuan, Director of Central Lab of Beijing Research Institute for Tuberculosis Control)
From the chart, we can see that most molecular detection method is expensive, sensitive, fast and complicated, which has obstacle in promoting. Also, it is shown that by sputum smear TB is hard to be detected, and it takes lots of time to test. But there are far more people who use sputum smear than people who use molecular detection method due to the policy and budget.
2.Competitive situation of the TB detection products
Although TB testing is still reliant on traditional tools such as sputum smear microscopy and culture, new detection methods are changing the tuberculosis diagnostics landscape. The 2014 UNITAID TB Diagnostics Technology and Market Landscape report listed the technologies endorsed by WHO[2], stated that it should be noted that the most impressive trend is the application of molecular technologies in TB testing, such as traditional PCR, RT-PCR, Gene microarray and X-pert, which have already entered the Chinese market.
According to Director Ding, patients using the advanced molecular testing methods accounts for only 4.3% of all patients in Beijing, while sputum smear and culture is still the common method. Of the nucleic acid detection methods, the percentage of X-pert takes up 72%. It is clear that molecular testing method is not as popular as sputum smear and culture in China since sputum culture is much cheaper, which has been regarded as the golden criteria for years and covered by health insurance. However, sputum smear is not sensitive enough particularly in those with HIV and in children. Note that among 7271 cases reported in 2014, only less than 3000 were smear-positive TB.
3.Competitive analysis of common nucleic acid detection products.
Table 2. Comparison of current RT-PCR kits.
From the chart, we can see that there are no differences among sensitivity and specificity in almost every product. If we want to share market volume with relatively mature products, we need to make efforts to cut the cost, and that’s why we construct the portable device that is cheap and user-friendly.
4.Substitutability of competitive technologies
The principles of current detection methods fall into three categories. Bacteriological methods such as sputum smear microscopy, mycobacteria culture and isolation identification recognize TB directly and identify the species of TB in the meantime. Sputum is cheap but not sensitive enough, while culture serves as reference standard but takes weeks; Immunology method based on detection of antibody in serum is fast and easy to operate but indirect, which is not recommended as a routine diagnostic method by WHO for its low sensitivity and specificity; Molecular biological methods detects specific sequence of TB directly, having the advantage of rapidness and sensitivity. However, its high cost of reagents and requirements on facilities and operating skills is the major obstacle for promotion. Compared with existing detection methods, our device is of sensitivity, specificity, portability and programmability.
Demand in TB diagnosis market
China has an urgent demand of reliable TB diagnostic technology. According to the fifth national tuberculosis epidemiological survey, 2010, three features characterize the epidemic situation of tuberculosis in China.
- Morbidity in rural areas is significantly higher than that in cities, which are 569 and 307 per 100 thousand people respectively.
- 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.
- It is estimated that there are nearly 5 million active pulmonary tuberculosis patients above 15 years old.
Institutes in all levels of TB control and hospitals of all types are target customers of our product, particularly community hospitals and clinics, where equipped laboratories and funding are usually lacked. Note that 30 million yuan was invested into institutes of TB control of Beijing, while just 2.5 million yuan for those of Hebei Province.
Director Ding mentioned that one of the important factors influencing customers’ behaviors is the convenience of operation process. It is supported by the fact that molecular detection methods was popularized by Beijing government since 1994, however, only 2 institutes were equipped with the platform due to its complex operation process and high cost.
Figure 1. Features that a detection method is supposed to have.
Based on the data above, DCF valuation method is used to predict the value of our product on the assumption that our product enters the market.
(1) Price estimate: the cost of our device and kits is around 100 yuan per time. The device, which can be repeatedly used, is about 200 yuan and belongs to the fixed costs.
(2) The first year of sales:
Table 3. Prevalence Rate of TB in China, 2007-2013
(Data from the National Bureau of Statistics[3])
According to the data provided by the National Bureau of Statistics above, we predict the incidence of the next five years by linear regression.
Figure 2. Linear repression of the prevalence rate, 2007-2013.
Figure 3. Linear repression of the total population in China, 2007-2013.
Table 4. Prediction of prevalence rate, total population and incidence in 5 years.
To sum up, we predict that there will be about 3,500,000 incidents cases in China the next five years. Given that the use of molecular testing method accounts for 4.17% in Beijing last year, which is ahead the whole country, we assume that all provinces will ultimately reach that rate due to the promotion of molecular detection in 5 years. And why our product can be promoted very fast? Because 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. So it could be estimated that there will be about 60,000 patients expected to utilize the technology in the whole country and the capacity of molecular detection market is more than 6,000,000 Yuan. If we count the patients who should be tested again when they recovered after treatment, the market capacity is going to be expanded.
As capacity of the first sales’ cycle amounts to 6 million yuan, considering that the costs of our product is 80 yuan for single use, the cash flow will be approximately 1-2 million Yuan per year.
References:
1. WHO. Global Tuberculosis Report 2014[M]. World Health Organization, 2014.
2. Wang L X, Cheng S M, Chen M T, et al. The fifth national tuberculosis epidemiological survey in 2010[J]. Chinese Journal of Antituberculosis, 2012, 34: 485-508.
3.http://data.stats.gov.cn/easyquery.htm?cn=C01&zb=A0O0F01&sj=2014
http://data.stats.gov.cn/easyquery.htm?cn=C01&zb=A0301&sj=2014