Embryonic Stem Cell Research in China

Policy Brief

Principal Editors^[1]

Amanda Dickins

Centre for Biomedicine and Society

School of Social Science & Public Policy

King’s College London

Aaron D. Levine

School of Public Policy

Georgia Institute of Technology

What is Embryonic Stem Cell Research?

The promise of embryonic stem cell research

Human embryonic stem cells (hESCs) were first successfully isolated and maintained in an undifferentiated state in 1998. [1] Because in normal development, these cells give rise to all cells in a mature organism, the isolation of hESCs was seen as an important step toward the development of novel transplantation therapies and a key element in the emergence of regenerative medicine [2] – a broader medical paradigm of which hESCs are one part.

The idea behind these potential hESC-based therapies is straightforward. In principle, scientists can coax undifferentiated hESCs to differentiate preferentially into specific cell types of interest (e.g. neurons, pancreatic cells, etc.) and these cells can be used for transplantation. This approach is seen as having the potential to benefit a range of patients; those suffering from Parkinson’s and diabetes are typically mentioned. Although this therapeutic approach is relatively straightforward in concept, it is difficult in practice. Key challenges include isolating pure populations of cells suitable for transplantation and ensuring hESC-derived cells integrate and function properly following transplantation. These questions are the subject of active research for scientists working both with hESCs and comparable mouse cells and substantial progress has been made, though many challenges remain. (The state of hESC science is reviewed in a 2006 NIH report: Regenerative Medicine).

This idea of hESCs leading to transplantation therapies is closely linked with another technology, called somatic cell nuclear transfer (SCNT). This approach relies on SCNT to create embryos genetically identical to patients. These embryos could, in principle, be used to develop hESC lines genetically-matched to specific patients, reducing or eliminating immune rejection – a key difficulty with most existing transplant therapies. This technique could also provide a means to develop hESC lines from patients with specific diseases. Disease-specific hESC lines exist for a number of genetic diseases, such as cystic fibrosis, today, but SCNT may permit this technique to be used for a broader range of illnesses, including those without a clear genetic basis. To date, scientists have not yet developed hESCs using SCNT, but recent reports indicate progress toward this goal [3] and the technique is routinely used with mouse cells.

Beyond this medical potential, hESCs are a powerful tool to understand human development. Because studying human embryonic development in vivo is essentially impossible, hESCs provide a unique opportunity to understand how cells develop and differentiate and offer scientists an opportunity to study embryo implantation, embryonic development and related processes. This understanding may well have important implications for fertility medicine.

In addition to these benefits, hESCs are also seen to offer new strategies for drug testing. In particular, hESCs may provide a means to rapidly screen potential therapeutic compounds for toxicity. Pharmaceutical firms testing potential medicines often rely on animal models for preliminary toxicity testing and initial studies have suggested that testing potential drug candidates with stem cells could offer benefits over the current system.

In part because it offers the potential for benefits in a variety of areas, hESC research has received significant attention since these cells were first isolated. Scientists have made substantial progress working with the cells, both in humans and with comparable cells in animal models. These advances have spurred continued interest in the field on the part of scientists, patient advocates and policymakers. Key challenges remain and the future impact of the cells – particularly in regard to the development of medical therapies – remains an open question.

The ethical controversy surrounding embryonic stem cell research

The potential of hESCs outlined in the previous section must be balanced with the ethical controversy the field generates. Ethical controversy arises in regard to this research because the process of isolating hESCs from early embryos typically renders these embryos unviable. Individual views differ on the moral status of early human embryos, but among the subset of the population who grant human embryos moral status equal to mature humans, isolating hESCs is morally equivalent to abortion or even murder.

To understand more fully the ethical debate over hESC research, it is important to consider the various sources of embryos used in this research, as many people distinguish between various sources when evaluating the ethics of this field and government policies often draw distinctions based on these different sources. Table 1 lists the three major sources of embryos available for hESC research and summarizes the ethical arguments made in favor of each. These three sources are hESC lines derived through SCNT, hESC lines derived from embryos created solely for research using in vitro fertilization (IVF), and hESC lines derived from IVF embryos originally created, but no longer needed, for fertility treatment. The majority of hESC research completed to date has relied on this latter category of embryos, so-called “supernumerary” or “extra” embryos, which would presumably be destroyed if not used for research. The exact number of frozen embryos stored in fertility clinics is unknown, but a 2003 study suggested roughly 400,000 were stored in the United States [4] and a recent report suggested a growing number existed in China. [5]

Table 1 – Sources of embryos for hESC research

Because the use of human embryos in research is controversial, ethicists, policymakers and scientists have been interested in identifying alternative approaches that would offer some, if not all, of the benefits of hESC research without requiring the destruction of human embryos. The most notable of these alternatives is known as somatic cell reprogramming and was first demonstrated with mouse cells by Shinya Yamanaka (New York Times Profile) at the University of Kyoto [6]. More recently Yamanaka and his colleagues as well as a U.S.-based research group led by James Thomson at the University of Wisconsin have demonstrated the technique with human cells [7, 8]. Somatic cell reprogramming works by converting skin cells into cells that have properties similar to hESCs. In particular, these induced pluripotent cells (or “IPS cells” as they are called) can give rise to cells in a variety of different tissues from all three germ layers and, thus, appear to offer many of the benefits of hESCs. The reprogramming process is poorly understood, but relies on the genetic modification of skin cells through the insertion of four genes. Although IPS cells are much less controversial than hESCs, the genetic modification techniques used in the reprogramming process raise health and safety issues that must be addressed before any therapies could be developed using these cells.

The policy environment for embryonic stem cell research

Because of the unusual combination of scientific potential and ethical controversy it generates, hESC research is governed by a diverse set of policies in countries around the world. [9, 10] Some countries have decided that hESC research is morally acceptable or that its potential outweighs any ethical concerns and are actively encouraging research in the field. Others have reached the opposite conclusion and essentially ban all hESC research. Finally, a large number of countries fall between these two extremes and have adopted compromise policies, permitting some elements of hESC research, while restricting others. Policy may also vary at the sub-national level. This is particular important in the United States, where hESC science has emerged as an important state policy issue with several states, led by California, actively supporting research in the field, while other states explicitly block most, if not all, hESC research. Table 2 summarizes policies in a range of countries around the world and in U.S. states.

Policy type	Countries and states
Permissive (eg, SCNT is specifically permitted under certain conditions)	Australia, Belgium, China (People’s Republic), Finland , India, Israel, Japan, Singapore, South Korea, Sweden, South Africa, United Kingdom US: California, Connecticut, Illinois, Maryland, Massachusetts, Missouri , New Jersey, Rhode Island
Permissive Compromise (eg SCNT is prohibited; hESC research using supernumerary IVF embryos is specifically permitted or not prohibited)	Argentina, Brazil, Bulgaria, Canada, China (Hong Kong), Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland , France, Georgia, Greece, Hungary, Iceland, Iran, Latvia, Moldova, Netherlands, New Zealand, Portugal, Romania, Russian Federation, San Marino, Slovenia, Spain, Switzerland, Taiwan, Turkey US: Arkansas, Indiana, Iowa, New Hampshire, Virginia
Restrictive Compromise (eg hESC research only permitted using cell lines created before a certain date)	Germany, Italy
Prohibitive (eg research using embryos or cell products derived from embryos is prohibited)	Austria, Colombia *, Costa Rica *, Ecuador *, El Salvador *, Lithuania, Norway, Panama *, Peru *, Poland, Tunisia, Slovakia US: Florida, Louisiana, Maine, Michigan, Minnesota, North Dakota, Pennsylvania, South Dakota

Table 2 – Policies toward hESC research

Source: Hinxton Group (which maintains an updated list online.) Also see the International Society for Stem Cell Research policy database.

As can be seen in Table 2, China falls into the most permissive policy category. This places China among countries supporting the field and trying to develop and grow their hESC research communities. Recent reports on hESC research and regenerative medicine in China indicate that China is vigorously pursuing the development of regenerative medicine and some claim that it is "emerging as the new superpower of biomedical research." [11] A group of Chinese stem cell scientists have offered the opinion that "no country is pursuing the field more aggressively than China." [12] A 2004 UK mission investigating the state of stem cell research in China found that it was "competitive", with new groups undertaking "international quality science… at, or approaching, the forefront of international stem cell research." [13] The importance of China for regenerative medicine is predicted to rise as the field moves towards translational research: the 2004 mission observed a strong drive to apply stem cell research in the clinic and a 2007 report suggested that China could "lead the world" in "applying [stem cell] research in clinical settings." [14] The remainder of this policy brief focuses specifically on embryonic stem cell research in China and aims to provide insight into the nature of China’s efforts in this field and an understanding of the extent to which these efforts have been successful.

Embryonic stem cell research in China

As noted above, governments around the world (including state governments in the United States) have made different decisions regarding the extent to which they support or restrict hESC research. Governments that have chosen to support hESC research have further policy decisions to make. These include the development of an ethical oversight system and decisions about how to fund hESC research. This section initially examines the ethical oversight and funding mechanisms used for hESC research in China and then discusses China’s performance in the field so far.

Ethical oversight

In China, hESC research is primarily regulated at the national level by ministerial guidelines, the "Ethical Guiding Principles on Human Embryonic Stem Cell Research." (Link to unauthorized translation. Official translation should be available in late 2008.) These guidelines prohibit the development of embryos beyond 14 days and they also stipulate that embryos used for research purposes cannot be implanted into a human (or any other animal). The Chinese guidelines for hESC research prohibit the buying and selling of human eggs, sperm, embryos and fetal tissue and stipulate that all gametes and tissues must be voluntarily donated and that informed consent is required.

In addition, the "supply side" of hESC research is governed in greater detail by regulations on reproductive medicine (unauthorized translation). These regulations specify that super-stimulation, as opposed to therapeutic stimulation, of the ovaries is forbidden. [15] Embryos can only be created for the purpose of procreation and they can only be used by the couple who created them, they cannot be donated to another couple, even though China’s one-child policy means that most couples undergoing IVF treatment will be unable to use such embryos for further reproduction.

Although the Chinese guidelines governing IVF and hESC research state that informed consent must be obtained from the ‘subject’ of such research, the guidelines do not distinguish the procedure for obtaining consent to donate from consent for the IVF treatment. Even in leading IVF clinics, consent to donate may be obtained simply by the patient placing a mark in a check box on the consent form for the treatment itself.

With respect to the combination of human and animal material to create embryos, the Chinese regulations clearly prohibit the hybridization of germ cells. However, it is not clear whether SCNT using animal eggs and human nuclei is currently permissible in China. Such work was performed in the past – prior to the promulgation of the national guidelines for hESC research – by SHENG Huizhen and her colleagues [16]. It appears that this matter is currently under consideration at the Ministry of Health (see forthcoming report from the UK Medical Research Council – “China-UK Research Ethics” committee).

Implementation is a key issue in assessing the regulation of research ethics in China because China’s regulations mostly consist of guidelines promulgated by the relevant ministries. Although there are sanctions available to punish violations (discussed further below), these ministry guidelines have less authority than formal laws passed by China’s legislature, the National People's Congress, or regulations promulgated by the State Council (the highest organ of the central government).

Researchers applying for funding from major state funding programs (such as the Ministry of Science and Technology’s 863 or 973 programs discussed below) are required to make a statement that they will follow the guidelines in their proposed research. Although the guidelines do not carry the same precise status as law, a researcher who failed to comply with the relevant guidelines could face a warning or lose their funding and they might even face a fine or lose their job (see forthcoming report from the UK Medical Research Council – “China-UK Research Ethics” committee). The range of potential punishments includes "open criticism" or the withdrawal or termination of qualifications or work. The withdrawal of licenses would be a serious punishment because it is illegal for clinicians or medical institutions (including IVF clinics) to operate without a government license. The withdrawal of licenses has been used to punish violations of, for example, guidelines on reproductive medicine.

However, the hESC guidelines do not include any provision for monitoring or inspection to ensure that researchers adhere to the guidelines. (There is national oversight of the reproductive medicine regulations via the licensing system for IVF centers.) Moreover, the hESC guidelines are couched in general terms and lack detailed codes or protocols for implementation. They merely require research institutions to formulate “detailed measures and regulatory rules” and establish an ethical committee to supervise hESC research. So, although the regulations may look impressive on paper, there is no system in place to uncover compliance failures. In the absence of external monitoring, adherence to guidelines depends on the integrity and governance structures of individual institutions and their staffs.

Informal conversations with Chinese stem cell scientists indicate that those scientists working near the research frontier and seeking to contribute to English-language journals have strong incentives to follow or even exceed national standards. Other scientists may have less incentive to follow these guidelines.

Institutions conducting hESC research are obliged to create an ethics committee to govern the research but there are reasons to be concerned by the reliance on such committees. Although the field of bioethics has developed rapidly in China, much remains to be done in terms of capacity building and ethical expertise may not always be available at individual institutions. The Ministry of Health’s committee of bioethics experts operates in advisory capacity and may be able to assist on particularly difficult issues. Moreover the guidelines require that the ethics committee must provide scientific as well as ethical review, which may give rise to confusion and even conflicts of interest.

In summary, China’s guidelines for hESC research are broadly similar to those adopted in western nations, such as the United Kingdom, supporting research in this field. However, despite the similarities in terms of which research practices are permitted or restricted, China’s oversight mechanisms are less formal and there is less attention to licensing and enforcement issues.

Funding

Accurately assessing China’s investment in stem cell research in general and hESC research in particular is difficult. This difficulty arises for several reasons, including the diversity of sources for research funding and difficulties estimating the actual in-country purchasing power of Chinese currency, the yuan or renminbi (RMB). The major funding national source for research funding in China is the Ministry of Science and Technology (MOST). In addition to MOST, the Natural Science Foundation of China (NNSF) provides funding for basic research and the Chinese Academy of Sciences (CAS) conducts a substantial amount of research. Municipal and provincial governments, particularly in Beijing and Shanghai, also fund scientific research. (China’s R&D system was recently reviewed in a discussion of China’s role in the global stem cell bioeconomy. [17])

Given these challenges, estimates of China's annual investment in stem cell research must be viewed with some uncertainty. The most frequently-cited estimates derive from a December 2005 report by the UK Stem Cell Initiative (known as the Pattison Report). This report estimated that China’s annual investment in stem cell research was somewhere in the range between US $4-10 million (~$9-24 million based on purchasing power parity ) with 300 researchers working in 30 separate institutions. It also reported that these figures were projected to increase dramatically. Estimates quoted in the UK’s Pattison Report suggest that over the next five years (2006-2010), MOST, was expected to spend between RMB 500 million (~$61 million based on market exchange rate, ~$145 million based on purchasing power parity ) and RMB 2 billion (~$245 million market exchange rate, $580 million purchasing power parity ) (see online supplement to the Pattison report). Much of this funding from MOST will likely be channeled through two of its major programs: the High Technology R&D program (the 863 Program) and the National Basic Research Program (the 986 Program). China has, for instance, identified biotechnology as a key focus area for its investment in R&D and both the 863 and 973 Programs have included funding for biotechnology in general and stem cell science more specifically.

More recent estimates of Chinese funding for this field are not generally available, leaving the extent of this growth in funding rather uncertain. Details may appear on the English-version of the MOST website in the future, but current pages for the 863 Program and the 973 Program have not yet been updated to reflect the 11^th Five-Year Plan, which runs from 2006-2010. Given this uncertainty it is difficult to assess how China’s funding for stem cell research in general or hESC research more specifically compares with other countries.

Leading scientists

Similar to the challenges associated with quantifying China’s total expenditures on stem cell research, it is difficult to identify the full set of scientists working on this field. Estimates from the 2005 UK stem cell initiative report suggested that China had roughly 300 scientists working on stem cell research. This number has likely grown in recent years.

While a complete enumeration of Chinese stem cell scientists is beyond the scope of this policy brief, a selection of some of the leading stem cell scientists in China is presented in Table 3. This listing focuses on scientists leading research groups active in hESC research or working in closely-related fields.

Table 3 – Partial listing of Chinese scientists working on hESC or related research

Note: Name order details 

Research outputs

Because research publications are one of the major outputs of the biomedical research enterprise, assessments of China’s production of research articles provides one means to quantify China’s performance in this emerging field. Although several analyses of hESC research output have been published in the last few years, none has yet focused specifically on China.

Two systematic analyses have suggested that the United States research output in this field is lagging [18, 19] and one of these highlighted the growth of hESC research in Asian countries as a potential explanation of relative underperformance in the United States. [18]

More recently, two studies have looked at hESC research publications in isolation to assess the state of the field. A June 2006 report [20] looking at publications produced through the end of 2005 placed China fifth in the total number of publications produced describing experimental hESC research. In this analysis scientists based in China produced approximately 5 percent (16/315) of all hESC articles published from 1998 to 2005. A similar study conducted a year later found that China ranked sixth in the production of hESC articles. [21] In this study, China produced approximately 6 percent (32/530) of hESC articles published through April 2007. These data should be interpreted in light of China’s overall growth in research publications across all fields and particularly biomedicine. According to data reported in the National Science Foundation’s Science and Engineering Indicators 2008, China’s share of the world’s scientific and engineering research publications in all fields increased from 1.6 percent in 1995 to 5.9 percent in 2005.

In addition to the production of hESC articles, the development of new hESC lines is another important metric for assessing the status of research in the field in a given country. These lines are derived from embryos – the source of the ethical controversy surrounding this field – and form the raw material for most experiments. A single hESC line can be the basis for an essentially unlimited number of experiments. However, because each cell line may have different properties, there are advantages to having access to a number of different lines. The exact number of hESC lines produced in China is not precisely known, but it is clear that Chinese scientists have successfully developed some lines. The 2005 UK report, for instance, concluded that Chinese scientists had produced “10 or more” hESC lines. Another report, based on counting hESC lines reported in research articles published by December 2005, identified 21 hESC lines developed in China. [20] The research centre in Changsha works in close collaboration with a major IVF clinic and claims to have derived over 200 hESC lines, although most of these lines are not fully characterized.

These data on China’s performance in hESC research contribute to a picture of China as a rapidly emerging, but not dominant player in the field. China’s publication production is growing in hESC research, as it is in most other fields, and Chinese scientists are making some contributions at or near the research frontier.

Editors Note

Both editors contributed equally to this policy brief.  The editors gratefully acknowledge funding from the George Mason University U.S- China Cooperation Program in Science Policy, Research, and Education and the Global Politics of Human Embryonic Stem Cell Science project funded by the ESRC (reference RES-340-25-0001) as part of its Stem Cell Programme.

Endnotes

1. Thomson, J.A., et al., Embryonic stem cell lines derived from human blastocysts. Science, 1998. 282(5391): p. 1145-7.
2. Mason, C. and P. Dunnill, A brief definition of regenerative medicine. Regen Med, 2008. 3(1): p. 1-5.
3. French, A.J., et al., Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells, 2008. 26(2): p. 485-93.
4. Hoffman, D.I., et al., Cryopreserved embryos in the United States and their availability for research. Fertility and Sterility, 2003. 79(5): p. 1063-9.
5. Heng, B.C., Growing surplus of frozen embryos in China offers opportunities for the development of human embryonic stem cell banking. Regenerative Medicine, 2007. 2(6): p. 873-874.
6. Takahashi, K. and S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 2006. 126(4): p. 663-76.
7. Takahashi, K., et al., Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007. 131(5): p. 861-72.
8. Yu, J., et al., Induced pluripotent stem cell lines derived from human somatic cells. Science, 2007. 318(5858): p. 1917-20.
9. Bosch, X., In Europe, as in US, climate for embryo stem cell research is one of extremes. Journal of the American Medical Association, 2005. 293(18): p. 2202-3.
10. Knowles, L.P., A Regulatory Patchwork--Human ES Cell Research Oversight. Nature Biotechnology, 2004. 22(2): p. 157-63.
11. Henderson, M., The Wild East is now tamed, in Times. 2007: London.
12. Liao, L.M., L.S. Li, and R.C. Zhao, Stem cell research in China. Philosophical Transactions of the Royal Society B-Biological Sciences, 2007. 362(1482): p. 1107-1112.
13. Du, J., et al., Stem cell mission to China, Singapore and South Korea: Report of a DTI Global Watch Mission. 2004.
14. Keeley, J. and J. Wilsdon, China: The Next Science Superpower?, in Atlas of Ideas, C. Leadbeater and J. Wilsdon, Editors. 2007.
15. Doring, O., Chinese researchers promote biomedical regulations: What are the motives of the biopolitical dawn in China and where are they heading? Kennedy Institute of Ethics Journal, 2004. 14(1): p. 39-46.
16. Chen, Y., et al., Embryonic stem cells generated by nuclear transfer of human somatic nuclei into rabbit oocytes. Cell Research, 2003. 13(4): p. 251-63.
17. Salter, B., M. Cooper, and A. Dickins, China and the global stem cell bioeconomy: an emerging political strategy? Regenerative Medicine, 2006. 1(5): p. 671-683.
18. Levine, A.D., Trends in the geographic distribution of human embryonic stem cell research. Politics and the Life Sciences, 2005. 23(2): p. 40-45.
19. Owen-Smith, J. and J. McCormick, An international gap in human ES cell research. Nature Biotechnology, 2006. 24: p. 391-392.
20. Guhr, A., et al., Current state of human embryonic stem cell research: An overview of cell lines and their use in experimental work. Stem Cells, 2006. 24(10): p. 2187-2191.
21. Winston, R.M.L., Does government regulation inhibit embryonic stem cell research and can it be effective? Cell Stem Cell, 2007. 1(1): p. 27-34.

Additional Notes

Finland is categorized with green and yellow stripes because the relevant law (The Act on Medical Research – No. 488/1999) does not consider the product of SCNT to be an embryo. This law explicitly allows for the use of supernumerary embryos for hESC research and it is understood that SCNT – as it is not prohibited – is permitted in the country.

The Missouri Stem Cell Research and Cures Initiative contains language that is very supportive of stem cell research, and while it prohibits human reproductive cloning and fertilization solely for the purposes of research, but allows researchers to conduct any research permitted under federal law. U.S. Federal law does not currently prohibit SCNT.

Categorization based on national policies extending a right to life to conceived or unborn persons. In the absence of specific exceptions, it is unclear whether the constitutional language would prohibit the destruction of embryos for any purpose, including research.

Purchasing power parity calculations are based on the World Bank’s 2005 International Comparison Program released in February 2008. This report estimated that $1 = 3.45 RMB using PPP compared with $1=8.19 RMB using market exchange rates. PPP was calculated for China based on a sample of 11 administrative areas that were extrapolated to the national level by the World Bank and the Asian Development Bank. Hong Kong, Macau and Taiwan are excluded from the PPP calculation.

It is Chinese tradition to list the family name first, although this is sometimes changed in English language documents to follow western convention. To avoid confusion, we have followed a common practice of putting the family name in upper case.