Introduction

Owing to its global dynamics, regulatory developments in regenerative medicine simultaneous repel and incorporate what is condemned as ‘unethical’. This chapter understands such regulatory boundary-work through the notions of regulatory immunity and regulatory tolerance (also see the introduction to Part II). Just as the notion of immunity emphasises the boundaries of the body or of the community, this approach to regulation emphasises the crucial role of the creation and ‘performance’ of regulatory boundaries in jurisdictions. After discussing the possibility of universal regulation of clinical stem cell provision, I will compare regulation for clinical applications of mesenchymal stem cells (MSCs) in the context of an LMIC (China) and in various HICs (US, Australia and the EU). Even though this comparison is very general, it will tell us something about the ways in which countries with different regulatory reputations and national income deal with scientific uncertainty and the ethics of ‘experimental’ interventions. It will become clear that countries, disregarding their regulatory reputation, find ways of circumventing the rules. My aim is to show that a country’s tolerance for regulatory flexibility depends on the international position and science policies in a global context. Finally, I will briefly discuss the call for regulatory harmonisation and global regulatory oversight through the World Health Organisation (WHO).

Regulatory boundaries in regenerative medicine came about when political authorities took over the responsibility from professional communities to regulate themselves. The various stakes scientists have in the political economy of their trade, characterised by fierce competition and strategic collaborations, make self-regulation a liability. The regulation of regenerative medicine facilitates and delimits what otherwise would be regarded as an experimental practice. Stipulating the conditions under which innovation takes place aims to optimally safeguard the rights and safety of patients and the quality of science. Without regulation, it is suspected, promising technological innovations would be imitated by profit-motivated copycats and traded in an uncontrollable manner. This fear leads regulators to stress the public importance of their legal responsibilities. For example, EU’s regulator EMA in the epigraph heading this chapter insists on the priority of patient protection in its 2007 Regulation (EC No 1394/2007).

Without regulation and standards, rivalry among providers of stem cell interventions could culminate in physical and mental harm to patients, financial loss, opportunity costs and anxiety about the reliability of such interventions. Its lack would also hamper the growth of scientific knowledge, as a difference in procedures would make a systematic comparison impossible. Though regulation has the potential to protect a stem cell community against violators, as we shall see, views on what are reliable stem cell interventions and scientific knowledge differ widely across regions. Moreover, what counts as the risk of physical and mental harm to patients, financial loss and opportunity costs also starkly differs. This means that countries require their regulation to do different jobs, and it is this that opens up structural spaces for competition.

I here use René Girard’s notion of ‘mimetic rivalry’, defined in the introduction to Part II as a form of competition based on self-identification with others, to characterise competition in the world of regenerative medicine, that is, imitating what are hyped as promising approaches in the field. New trends in life-science innovations are followed globally, some of which include the shift in clinical research focus from adult stem cell therapy, tissue-engineering, hESCR, gene-therapy and iPS to direct reprogramming, immunotherapy, stem/progenitor cell therapy and transplantation and a recent shift towards organ bioengineering utilising stem- and progenitor cells and genome-editing. These shifts are accompanied by new political decisions about project funding, research regulation and economic forecasts. As illustrated by a discussion from the House of Lords in the UK, such discussions are about global competition, regulation and national productivity:

To gain insight into relations between national ‘Selves’ vis-à-vis regenerative medicine and healthcare provision at home, on the one hand, and vis-à-vis their global position in the world, on the other, this chapter asks how frictions between national Selves and Non-Selves – that is, other jurisdictions – can be explained in terms of regulatory immunity and regulatory tolerance.

Since the 1980s, the growing importance of the reputation of regenerative medicine has increasingly cast doubt on the regulatory and ethical integrity of science (Carpenter Reference Carpenter2010). The US halt in 2001 to federal funding of research using new hESC lines for ethical reasons, for instance, shows that research regulation involved much more than the safety of patients and the efficacy of research. Protection against reputational risk (Larkin Reference Larkin2003; Sleeboom-Faulkner Reference Sleeboom-Faulkner2010) demanded that recipients of state funding would not just have a scientifically safe and sound research plan; ideally, they would also fulfill moral expectations, have publications in international peer-reviewed journals, perhaps engage in prestigious international science collaborations and have a good ‘scientific’ reputation, both internationally and at home. The same is true in countries often critically and strategically associated with ‘rogue’ science, such as China and India (see Chapter 1). China’s Ministry of Health (MoH) published formal guidelines for hESR in 2003 (Sleeboom-Faulkner 2008). Scientists involved in hESR felt the urge to distance themselves from both ‘muddlers in the countryside’ and from scientists engaging in Traditional Chinese Medicine (TCM) (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010). A leading stem cell scientist doubling as regulator in Beijing, for instance, accused a successful TCM scientist working on burn wounds of trading in snake-oil business, while the TCM scientist scolded established scientists for failing to see the body as a whole, as well as for wasting millions of government funding. In a global context, established Chinese scientists involved in hESR compared Chinese science favourably to its Western counterpart by pointing to China’s ‘scientific atheism’ being able to steer clear from anti-abortionists and to China’s highly capable leaders, who are engineers, rather than lawyers or actors (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010).

Scientific boundary-work (Gieryn Reference Gieryn1983) can tarnish reputations with far-reaching consequences. Chinese regulators have felt the need to combat ideas about China’s science community as the ‘Wild East’ (Bionet 2007; Zhai et al. Reference Zhai, Ng and Lie2016). A negative international reputation can weaken the credibility of a nation’s science, make it harder for scientists to get through peer review of international journals, make China less attractive for science collaboration with renowned science institutions and make it harder for Chinese scientists to defend the value of homegrown research ideas in a global setting (Sleeboom-Faulkner Reference Sleeboom-Faulkner2010; Zhang Reference Zhang2012). Under these conditions, it became important for China’s government to stimulate Chinese science institutions while at the same time defend the reputation of China’s pioneers, including its main target of international criticism for ‘stem cell tourism’: Beike Biotechnology Company or ‘Beike’. Beike was established in 2005 in Shenzhen. With 25,000 unauthorised treatments in its first decade (BeikeBiotech 2016b), Beike became a thorn in the side of both foreign and national elite laboratories in the field of regenerative medicine.

A global loss of the reputation of a research field might be blamed on the ethical recklessness of countries that try to forge ahead with controversial clinical applications no matter what (Tam Reference Tam2011; Salter et al. Reference Salter, Zhou and Datta2015; Chen Reference Chen2017). Cultures of scapegoating obtain when the ‘universal’ rules of the powerful are mobilised against violators to protect the reputation of the field. A globalised world, in which scientific self-regulation cannot be trusted and where global institutions that can enforce regulation are absent, cultures of scapegoating are fostered through mimetic rivalry, whereby some set the standards and others are expected to follow. Countries use regulation to protect the quality of scientific research and patients subject to clinical research and practices. The ascribed reputation of regulation, I refer to as ‘regulatory immunity’. Paradoxically, within the same jurisdiction, such regulatory immunity can go hand in hand with regulatory tolerance for unauthorised stem cell activities. Other countries may be accused of failing to implement regulation for these very same activities. In other words, the frictions between Self and Non-Self as embodied in regulatory values are internalised, requiring regulatory tolerance for regulatory ‘sin’. An exploration of regulatory immunity aims to clarify why countries decide to destroy and/or internalise what they condemn.

From approximately 2008, clinical stem cell providers have been criticised, reported and analysed by social scientists and the press (Kiatpongsan and Sipp Reference Kiatpongsan and Sipp2009; McMahon and Thorsteinsdottir Reference McMahon and Thorsteinsdóttir2010; Cyranoski Reference Cyranoski2012a). Governments in the US, Hungary, the Netherlands, Germany, Ireland, Belize and elsewhere closed down clinics that provided ‘unauthorised’ SCIs, while others failed to stop stem cell providers from charging high fees to administer ‘unproven therapies’ (Sipp Reference Sipp2009). The distinctions between ‘legitimate’ and ‘illegitimate’, ‘evidence-based’ and ‘traditional’ and ‘science-based’ and ‘experimental’ stem cell research and therapy have been subject to heated discussion among established scientists and critics. Observers make these distinctions to imply the existence of forms of stem cell research, applied by quacks, not to cure disease, but to exploit innocent mugs. Anthropologist Aditya Bharadwaj was among the first to question these distinctions in the context of India (Bharadwaj Reference Bharadwaj2013), criticising the binary between ‘kosher’ randomised control trials (RCTs) and ‘rogue’ stem cell clinics. As a result of the sharp and highly publicised distinction made between ‘universal RCTs’ and local forms of ‘rogue experimentation’, discussions failed to take into account the historical, cultural and political of these global developments.

Regulatory Tolerance in an LMIC: The Evolution of Beike Biotech Company

Examining the case of the stem cell company Beike Biotech in the PRC can shed light on how, under the global dynamics or regulatory capitalism, a large LMIC with global ambitions in the life sciences had to adopt ‘international’ regulation that did not suit its circumstances, thereby disabling its elite stem cell laboratories for years. In 2009, the plans for the adoption and development of ‘international’ standards in China culminated in a regulatory halt on all unauthorised SCIs; it took nearly six years for the government to develop implementable regulation that aimed to accommodate the needs of elite laboratories, industry and others (Zhang Reference Zhang2017; Li et al. Reference Li, Verter, Wang and Ning2019). As explained in Chapter 2, a number of clandestine stem cell providers continued to operate, but most state institutions closed down their clinical research practices in hospitals. There were exceptions, however, one of whom was Beike Biotech. Although a number of its branches stopped advertising its wares, the company continued to operate both internationally and in China.

In 2010, after the prohibition on stem cell clinics in 2009, it was announced in its Information Guide that Beike protocols utilise UC-MSC stem cells and recommending all MS and SCI patients to receive this type of stem cell injection ‘as the cells not only produce important growth factors and differentiate into desired cell types but can also regulate the immune system, reducing inflammation, scarring, and cell apoptosis’ (BeikeBiotech 2021b [2010]).Footnote ² Flying in the face of the 2009 regulations, it also claimed in its Information Guide that ‘China has been a pioneer in adult stem cell treatments for several years. The hospitals and medical staff working with and in Beike are experienced and confident in handling the stem cells and monitoring patients’ treatments’ (BeikeBiotech 2021b [2010]). As will become clear below, Beike’s activities were no secret to the government. So, what drives this kind of regulatory tolerance?

Around the same time, in Europe, Beike was well known for its ‘stem cell tourism’ and had a dubious scientific and ethical reputation as provider of SCIs for over a decade. One critic wrote:

But within China, Beike received sympathy, if not widespread support, including from investors, such as Beijing University, Hong Kong University of Science and Technology and Shenzhen’s Municipality (BeikeBiotech 2016). In 2012, when I visited Beike to find out why Chinese medical professionals, regulators and ethicists expressed confusion and surprise when I explained Beike’s image in Europe as ‘unethical’.

Beike attracts patients internationally through its therapy providing centre, through agencies for stem cell tourism and through websites. Most of its collaborative hospitals were private and endowed with various levels of luxury and treatment methods to cater to patients of different means and taste. Although Beike’s staff regarded therapy fees as ‘paltry compared to buying a car’ (Dong 22/4/2013*), for many patients the 30–100k RMB (c. 5–16k US$) paid for ‘treatment’ in 2013 was a fortune. Staff justified its prices in reference to the licensing fees levied by ‘American’ corporations, such as its AABB certificate (Dong 22/4/2013*). The fees of self-financing patients enabled Beike to continue its research. This contrasts starkly with similarly highly educated experts in state scientific institutes and hospitals, who usually do not have access to the funding. Although Beike did not have State Food & Drugs Administration (CFDA) permission, it had been conducting medical trials registered on the US NIH’s website (clinicaltrials.gov 2013) and received funding from the CFDA for its clinical trials through collaborations, such as its clinical trial for the treatment of systemic lupus erythematsus using UCMSCs (BeikeBiotech 2014). Other clinical trials were partly financed by provincial governments and cities, mostly conducted in private and in military hospitals (Deng, 25/4/2013*).

Although government regulation had prohibited unauthorised stem cell trials from 31 October 2009 through its new regulation on the risk management of medical technologies (Sui and Sleeboom-Faulkner Reference Sui and Sleeboom-Faulkner2015; Wu et al. Reference Wu, Chen, Wu, Pan, Xuan, Wei, Wang, Li and Song2016) and articles critical of stem cell tourism were appearing in the Chinese media (Lue 2013), Beike’s scientific image in China was not usually disputed. The majority of the discussions on ‘stem cell tourism’ in Chinese newspapers and on the Internet had been carefully censured. Conversations with scientists in 2012 and 2013 indicated that only the scientists that had part-time jobs abroad or had resided abroad for a prolonged period of time seemed to be aware of the poor scientific reputation Beike has outside China. These scientists mentioned the criticism that can also be found in the international media: not keeping medical records for outsiders to inspect, providing unproven therapies to patients, taking advantage of the placebo effect and not publishing its results in international science journals of reputation (e.g., Lim Reference Lim2008; McCullough Reference McCullough2008; Johnson Reference Johnson2010; Tam Reference Tam2011; Brown Reference Brown2012; Chen and Gottweis Reference Chen and Gottweis2013).

Such views were treated as false allegations by other scientists and policy-makers who had not lived abroad and who cite Beike Biotech’s website, articles and company events to counter them.

1. 1. Beike has built up a varied experience of therapy provision, simultaneously engaging in collaborative research and clinical trial, which has led to the joint publication of articles in international journals, for example, the Journal of Translational Medicine, PlosOne and Stem Cells (also see BeikeBiotech 2016a).

2. 2. In 2009, Beike was visited by Premier Wen Jiabao, who praised Beike’s scientific and therapeutic competence in comparison with the world’s most renowned life science hubs (Beikebiotech 2010).

3. 3. As for the placebo effect, interlocutors argued that if it is true that the scientific basis of stem cell therapies is not clearly understood yet, then it is also unclear whether any signs of improvement are attributable to the placebo effect (Gong, 10/7/2012*; He, 25/7/2012*; Gan, 21/6/2014*).

4. 4. Although patient records have not been maintained in the past, they are in 2012. But according to Dr Gong, they cannot be opened for inspection by competitors and audit for reasons of IPR and patient confidentiality (Gong, 10/7/2012*). Those who want to know more are referred to Beike’s website, which displays patient case studies (BeikeBiotech 2012a).

5. 5. Any queries about the provenance of the stem cells used in therapy are referred to the cord blood banks it runs and its connection networks (BeikeBiotech 2016c). Especially its collaboration with provincial governments in the management of provincial UCB banks and the state support it receives through grants and collaborations (BeikeBiotech 2016b) are cited to indicate Beike as a bastion of reliability (Gong, 10/7/2012*).

6. 6. Interlocutors refer to the world’s ‘highest certificate for blood banking’, referring to Beike’s AABB and other certifications and awards (Hao, 9/7/2012*; Lin, 9/7/2012*; BeikeBiotech 2016a).

High-profile interlocutors seemed to have no problem rebutting foreign criticism of Beike, many of whom referred to ‘China-bashing’ (Cai, 28/10/2012*).

The conditions under which patients had to pay for what are experimental therapies, interlocutors do not regard as unethical per se. After all, therapies falling outside China’s local healthcare provision lists are largely sold on a commercial basis, and total healthcare insurance coverage is rare. Patients are used to paying for private and authorised therapies. Furthermore, the practice of giving ‘red envelopes’ (bribes) to create goodwill is common (Yang Reference Yang2007), while patient choice of medical doctors/surgeons has become a right in China, for which many patients nevertheless also pay extra. The fact that Beike’s services attract ‘foreign’ patients, who for a long time paid twice the amount Chinese patients did (Dong, 22/4/2013*), was regarded as further proof in support of Beike’s reliability. Considering that there were no other affordable healthcare options for most patients, and that established life science centres did not receive permission to start phase I trials in stem cell applications (Chinese Academy of Science 2013), Beike’s provision of what has been criticised as experimental stem cell interventions were viewed by patients and scientists as a reasonable alternative and also for patients that do not suffer from life-threatening or intractable conditions (also see Salter et al. Reference Salter, Zhou and Datta2015).

It would be easy to condemn Beike Biotech as a jumbo snake-oil peddler for exorbitant pricing and preying on weak and desperate patients, and it would be easy to criticise China’s efforts at stem cell governance (Chen Reference Chen2017). Although one can be opposed to ‘unauthorised’ and ‘unproven’ SCIs for very good reasons, it is not very helpful to do so without taking into account Beike’s position in the global context of regulatory capitalism. China, as a large LMIC, in its efforts to ‘catch up’, just like other countries that do not want to ‘miss the boat’, mimic key innovators and try to adopt their regulations. Not having been involved in the creation of ‘international’ regulation in the first place, most of China’s state laboratories could not afford to adopt them. Working to adapt ‘international’ regulation and proclaiming a universal prohibition of unauthorised SCIs aimed to immunise the country against being labelled as rogue chancers. But the expenses and bureaucracy involved alienated the life-science industry, which, though engaging in the trade of biomaterials and equipment, largely refrained from involvement with clinical trials of stem cell interventions during the regulatory impasse from 2009 until 2015. Nevertheless, some regulatory violations were tolerated, if not celebrated.

Beike Biotech, run by biochemist (though better known as stem cell scientist) Xiang Hu, had good connections abroad and with scientific leaders of state laboratories and private hospitals. He was also a capable network-builder and scientist: he conducted research, gathered data, set up GMP-facilities, collaborated with universities and hospitals in clinical trials, engaged in umbilical cord banking (UCB) banking in various provinces and largely managed to collect its own funding. Beike’s role in China’s stem cell industry became increasingly important, and official support for Beike has not waned over time. In March 2014, Xiang Hu was invited to visit Germany with Chinese president Xi Jinping, and in the same year, 13 per cent of Beike was bought up by the other main industrialiser of regenerative medicine, Zhongyuan Union Stem Cell Bioengineering Corporation (Zhongyuan Union 2014). These two companies would champion the cause of industry during China’s regulatory struggles and exert substantial influence on the 2015 regulation (Rosemann and Sleeboom-Faulkner Reference Rosemann and Sleeboom-Faulkner2016; Zhang Reference Zhang2017; Li et al. Reference Li, Verter, Wang and Ning2019). Today, despite everything, scientific collaborations with Beike no longer seem to be taboo. The UK’s prestigious UKRI funds a project on ‘the role of pro-inflammatory mesenchymal stem cells in rheumatoid arthritis’ supported by its claim that it has ‘close collaborative links with industrial partners such as Beike Biotechnology, China’s leading biotechnology company on the development and commercialization of adult stem cell therapies’ (UKRI 2022). Although this might say more about the UKRI’s interests in ‘immunodeficiancy’, this certainly seems to lend credibility to formerly lambasted Beike Biotech.

In brief, China tried to immunise its clinical research into regenerative medicine by adopting what it saw as international regulation and adapting it. The impasse that followed created inactivity and uncertainty among its elite laboratories and frustrated the industrial sector. At the same time, however, China’s regulatory tolerance for Beike’s SCIs gave in to the development of what it saw as a promising industry, hoping for international recognition and to advance in stem cell science in the long run.

Regulatory Tolerance in HICs – Autologous Stem Cell Intervention

The notion of the West, if referring to modern, technologically advanced and well-regulated societies, is misleading. According to sociologist Bruno Latour ‘the West’ was never modern in the sense of society having emancipated itself from nature by means of science and technology (Latour Reference Latour1993); rather, any society should be seen as a construction of systems that mix politics, science, technology and nature. What is ‘technologically advanced’, then, is disputable, as advancement has to be measured against what people wish their society to be like. Nevertheless, if we can associate ‘state-of-the-art’ and ‘cutting-edge technologies’ with ‘advanced’ industrialised societies, we must also conclude that the world no longer has a single technologically advanced centre. The view that countries outside of the US and Europe are scientifically and technologically advanced has become increasingly accepted over the last century. But, whether they are ‘well regulated’ or not is very much contested, and there is no global agreement about what it means to be ‘well regulated’.

In Chapter 1, we have already seen that the notion of ‘deregulation’ can be confusing, if it denotes a liberation from bureaucratic obstacles to the scientific investigation of promising therapies. For what is usually referred to as ‘deregulation’ is directed at defining the conditions under which new scientific practices are enabled. In fact, the notions of ‘prohibitive’ and ‘permissive’ regulation, though not accurate, better reflect the dimension of enablement, which I believe is an important underlying motivation for regulating new clinical stem cell applications. Examining examples of regulatory immunisation and regulatory tolerance in ‘the West’ may give us insight into the politics of regulation. In this arena, we find that cliché concepts of patients, scientists and entrepreneurs are mobilised as pawns in the overhyped arena of regenerative medicine. After the discussion of regulatory boundary-work, I will reflect on whether global regulatory harmonisation can offer a way out.

Regulatory Tolerance – Should There Be Global Oversight?

In this chapter, I looked at how countries with different scientific institutional histories and income levels have dealt with scientific uncertainty and the ethics of ‘experimental’ interventions using so-called MSCs. Examining regulatory practices for clinical research and commercial interventions in the context of global competition, I took account of the complex intertwinement of the desirables of catering to patient needs and demands, the protection of high quality scientific research, the affordability of testing methods and the prospect of economic growth through investment into regenerative medicine in an LMIC and in HICs. The desirables of catering to patient needs and demands and the protection of high quality science underpin regulatory ideals, while affordability and economic returns on investment are often viewed as a matter of political preference.

HICs that traditionally have had the power to define standards and conditions set by regulation, even when that power is on the wane, still seem to enjoy considerable regulatory immunity. Nevertheless, we saw that HICs have been adept at creating regulatory clauses to soften their regulation and that they have shown substantial regulatory tolerance for violations. In HICs, a scientific boundary is commonly asserted between established stem cell scientists and clinical research providers that spoil the broth by not sticking to the official recipe. Scapegoating, here, is used as means to defend the reputation of the regulated collective against unauthorised stem cell clinics. Examples show that especially the US and the EU have used regulatory immunisation to protect the stem cell community’s reputation against violators. This immunisation effort included provisions for ‘regulated exemptions’ under which experimentation, condemned under other circumstances, can take place in a controlled manner. The mushrooming of stem cell clinics in the US for this reason has become a hotly disputed topic. In the EU, where countries seem to have various attitudes towards unauthorised stem cell clinics (EBE 2011; European Commission 2014), there is great sensitivity regarding official dissidence, as was illustrated by the case of Italy’s support for Stamina.

We also saw that regulatory immunised countries can afford to tolerate clinical research combined with therapy provision. Thus, the US and EMA immunised their established stem cell communities, making provisions for exemptions and accelerated pathways at the same time. Australia’s regulatory reputation, however, has been tarnished by minimally regulating autologous therapies as Therapeutic Goods. Hampered by its limited capacity to set up expensive clinical trials with its small-size population, the Therapeutic Good regulation afforded a way for research clinics to grow and compete outside its regulatory pathways for Biologics. This fed into Australia’s regenerative medicine capacity, especially when shielded by and integrated with international collaboration. In this way, the Therapeutic Goods regulation sidestepped the need for regulatory tolerance. The regulatory reforms of Australia’ Therapeutic Goods regulation (TGA 2019), however, includes a much larger proportion of autologous cell products. Though intended to decrease the hidden stem cell industry (Foong Reference Foong2018), the new competition is has created might encourage collaborations between stem cell clinics and hospitals with little oversight to provide unsafe clinical research applications (Ghinea et al. Reference Ghinea, Munsie, Rudge and Stewart2020).

Rising power China for decades has had similar ambitions to rival HICs in the field of regenerative medicine. To gain global recognition, it has attempted to strengthen its regulatory immunity by adopting and adapting ‘international’ regulation. When, partly due to expenses associated with the regulation and local incommensurable priorities, it failed to implement it convincingly, China’s efforts to develop the field were met by both constructive advice and, especially, global prejudice. An analytical distinction between failing to ‘clamp down’ on small for-profit clinics offering stem cell interventions and an indirect support for large companies that combine research with stem cell provision, such as Beike, is needed. The example of Beike shows why universal regulation is problematic to large LMICs that have the political ambition to become a global power in the field of regenerative medicine. Not being able to fulfill HIC regulatory requirements drove the PRC to tolerate Beike’s regulatory violations and led scientists from elite laboratories to blame Beike for tainting the reputation of both the field and China. It is not surprising, then, that there has been much regret among scientists outside the US and the EU that there has been relatively little ‘outsider’ say in the creation of regulation for stem cell science.

Ironically, a decade later, many of China’s dilemmas turn out to be endemic to the US: illegal stem cell clinics treating ‘no-option patients’ and patients without healthcare insurance. And, it is especially the exponential increase of mushrooming direct to consumer (DTC) clinics in the US that has prompted scholars to recognise the WHO as a global regulator of regenerative medicine. Master et al. (Reference Master, Matthews and Abou-El-Enein2021) argue that there is a diminishing trust in government institutions, such as the FDA and EMA, as a result of their inability to tackle harmful DTC of stem cell interventions. They maintain that the FDA, the US Federal Trade Commission (FTC) and state Attorneys General do not have enough clout to enforce regulation and to prevent the mushrooming of stem cell clinics. The main tasks of the WTO on regenerative medicine would be, first, ‘the harmonization of regulatory definitions and practices for cell-based therapies’; second, ‘using existing policies and regulations as a model’, it ‘could develop a regulatory framework or template regulations for countries to adopt’; and, third, it ‘would allow industry and clinics to understand more fully what techniques and products will be regulated and what is considered outside the scope of regulatory oversight’.

The proposal to have the WHO as main global regulatory authority assumes the use of a regulatory template based on US and EMA regulation and presumes that the rest of the world would follow. Again, we know that under regulatory capitalism, the designers of international regulation have a competitive advantage. If the WHO were to be in a position to take charge, it would do so, partly, because the US as major funder sets the agenda. But the WHO does not have the power to impose health policies on national governments: it is unlikely that the WHO would have more regulatory clout than the FDA in that country. Rather than trying to create a new but feeble global institutional ‘authority’, as I will argue in Chapter 9, we need to rethink the way in which science and science regulation are currently shaped through national competition and international collaborations.

In regulatory capitalism, regulation is part of the competitive arena, which requires a constant effort at regulatory delineation from (‘inferior’) others, that is, boundary-work. The binary between ethical and unethical research practices, then, is relevant not just as rhetorical medium but also as instrumental in steering the direction of innovation in regenerative medicine. For instance, prominent scientists in HICs still accuse the ‘Far East’ of spoiling the field of regenerative medicine, by dint of which they recommend regulatory enablement, before ‘They’ will start experimenting with immature clinical applications. Such boundary-work, as the next chapters shall confirm, is politically necessary both to maintain a competitive edge and to productively collaborate internationally. But without credible transcendental authority in a world dominated by regulatory capitalism, rather than protecting patient health, the regulation fails to safeguard the procedures and qualities of science that protect them.

Introduction

As shown in Chapter 1, HICs and LMICs tend to engage in different regulatory boundary-work. But even though elite laboratories in HICs scapegoat countries with ‘inferior’ regulation, some players in HICs, including the state, display a surprising measure of regulatory tolerance in their wish to engage in collaboration with the very same countries. Much of what we regard as ‘global’ collaboration is in fact ‘international’ collaboration, especially when it is the differences in national conditions that enable the collaboration. This chapter’s case study on international science collaboration between scientists in Chulalongkorn University (Chula) in Bangkok and scientists and managers of Kawasaki Heavy Industry (KHI) from Kobe and other cities shows how competitive desire incentivises international science collaboration. Although the collaboration is formed around a mutual interest in the development of a cell processing robot, important to industry and medical experts, it was largely enabled by differences in regulation, scientific expertise, available patient pools and material capacity. The collaboration did not just involve scientific interests, it also concerned the interests of the Thai and Japanese states.

The project around which the collaboration evolves received state support in both countries. This raises three questions pertinent to regulatory capitalism. First, how does regulation figure in negotiations between the two institutions/countries? To examine this question, I treat regulation as a form of capital that is negotiated. Second, how is science collaboration brokered in a context of regulatory capitalism, which is based on global competition? By examining how regulation figures as capital in international collaboration in a world propelled by regulated competition, I aim to show how the desire to collaborate and to compete form part of the same process. Third, how does international science collaboration based on regulatory discrepancy affect regulatory immunity? If countries collaborate based on the knowledge that they transgress the spirit of their own regulation, how does the immunitary politics around this collaboration impact the credibility of regulatory regimes?

A huge robotic machine was unveiled to the public on 30 September 2013 at a formal ceremony in Bangkok attended by scientists, company CEOs and officials from Japan and Thailand, including, the then Crown Princess Sirindhorn and the Japanese Ambassador to Thailand (Chulalongkorn University 2013). The robotic cell-processing machine, R-CPX, is core to a joint research collaboration between Chulalongkorn University and Kawasaki Heavy Industry (KHI) with the aim to conduct clinical trials for osteoarthritis treatment in Thailand. The clinical trials were expected to reveal that cells subjected to automated up-scaling using R-CPX could be a safe and efficacious basis for marketable therapeutic products. The robotic machine was installed at a research centre at Chulalongkorn University, which I name THAI [pseudonym]), by KHI, with financial support from the Thai government and Japan’s Department of New Energy and Industrial Technology Development Organization (NEDO).

But what brought Japan to collaborate with Thailand on this? Stem cell and ‘medical tourism’ in Thailand have long been criticised for profiteering at the expense of patients (Kiatpongsan and Sipp Reference Kiatpongsan and Sipp2008; Coghlan Reference Coghlan2010), an image it continues to struggle with. Despite adjustments to its regulation of business advertising (Wangkiat Reference Wangkiat2015), it has not been able to shake off its image of snake-oil provider (e.g., Thailand Medical News 2019) and continues to be scapegoated for damaging the reputation of regenerative medicine. In Thailand, however, ‘cell therapies’ on offer generally involve private clinics or hospitals, not elite research centres such as THAI. Speaking with the Japanese scientist who first worked on the robotic machine, I soon realised that a regulatory discrepancy between Japan and Thailand had been a major incentive for KHI to initiate the collaboration: the regulatory discrepancy became capital in the scientific collaboration.

When trying to understand the dynamics of global powers, there is a temptation to view the notions of competition and collaboration as opposites, while in fact, conflict and cooperation emerge together when forging of social relations. Conflict, according to philosopher Paul Demouchel, takes shape in the context of cooperation between those with conflicting interests. To occur in the first place, conflict requires some form of order or coordination of interests. I argue that, in a world characterised by competition, regulation is what binds different countries, especially when their regulations diverge. Collaboration thrives under regulatory discrepancy, as it affords exchanges to take place, not just related to regulation but also in relation to other ‘inequalities’, such as those pertaining to infrastructures and production resources, such as scientific and medical expertise, financial resources, healthcare provision and insurance systems. Such exchange involves acute awareness of the regulatory conditions and cultures and other difference involved.

Science collaboration, therefore, is not simply a question of pooling assets and bundling efforts to achieve a shared scientific goal. Rather, it involves a scrutinisation of how socio-economic, political and regulatory conditions enable available resources to be used to satisfy a range of goals, many of which may not be shared. Regulation from this angle is a form of capital negotiated, not just between institutions but also between the converging and diverging conditions in diverging regulatory jurisdictions. As we shall see, the mobilisation of regulatory capital also has consequences for our interpretation of the way collaborating countries are affected in the long run.

After introducing the notion of regulatory capital and the details of the collaboration around the robotic machine R-CPX, I will present four main themes of concern among Japanese and Thai scientists who were directly involved in the collaboration: science, medicine, economy and trust and regulation. The different takes by the collaborating partners on the four themes highlight points of competition within the collaborations and the way the collaboration serves a range of ends of which they only share some. The themes, as will become clear, either implicitly or explicitly, are contingent on the way in which regulatory capital has enabled this international collaboration. Finally, I will discuss the implications of this regulatory capital–based collaboration for the regulatory immunity of both countries.

Following the example of the memoranda of understanding (MOUs) between the collaborating partners, I refer to them as ‘Thai Team’ and ‘Japan Team’, which reverberates with the self-identification of Thai and Japanese interlocutors.

Regulatory Capital and the Japanese–Thai Collaboration around R-CPX

The term regulatory capital, referring to regulation as negotiable in collaboration across regulatory jurisdictions, allows us to view regulation as part of a collaboration, not just among institutions but also between countries. Much social-science work interprets scientific collaboration in positive terms of pooling assets to realise a common scientific plan (Shrum et al. Reference Shrum, Joel and Ivan2007; Shrum Reference Shrum, Parker, Vermeulen and Penders2010). But without an understanding of the potential drivers of collaboration, including regulatory and other discrepancies, such as available expertise, financial capital, health care provision and equipment, one fails to understand the dynamics of the collaboration and the conflicting interests that make the collaboration worthwhile.

The Japanese–Thai collaboration illustrates how regulatory discrepancy enables an international science project. Initially, a colleague drew my attention to the installment of the R-CPX in Bangkok. The regulatory discrepancy came to light when a Japanese scientist working on the R-CPX told me about their collaboration with Kawasaki Heavy Industry. KHI, in turn, explained that the collaboration was based on a win-win situation, enabling Thai scientists to conduct research using GLP equipment and allowing Japanese scientists to work toward clinical trials. To gain further understanding, I visited hospitals, companies and laboratories in Japan, the UK and Thailand between November 2013 and August 2014.

Thailand’s science policies in support of the development of regenerative medicine were designed to deal with widespread disease conditions, including thallasemia and heart disease. Investment into regenerative medicine was hoped to save public health spending in the long run. Although basic stem cell research is not unaffordable, for its results to gain international recognition, it needs considerable investment into the training of expertise, setting up GLP laboratories, high quality laboratory equipment and materials and administrative tools for governance and sophisticated regulation. Although Thailand announced its regulation for regenerative medicine in 2009, highly constrained financial budgets and a young life science community placed Thailand’s regenerative medicine on a weak footing. The intention of the science community was to strengthen Thailand’s international scientific reputation and to protect its budding international scientific collaborations, such as those with the EU.

For Thailand, then, its regulatory reputation was important. When KHI proposed the collaboration, reactions among scientists were mixed. The proposal seemed to confirm that Thailand’s community of regenerative medicine was viewed as robust enough to attract industrial scientists from Japan, a country then known for its prohibitive stem cell regulation. At the same time, however, KHI clearly indicated that its aim was to show that its robotic machine could process cells that were fit for clinical trials in Thailand, cells that, at the time, Japan’s regulators did not view as suitable for use in clinical trials. So, Thai regulation for regenerative medicine seemed strong enough for conducting international clinical trials, while at the same time it was weak enough for attracting collaborators from Japan.

This is how, lacking financial capital and scientific assets, Thai regulation became regulatory capital in negotiations that led to a collaboration between unequals. Although, within Thailand, various science institutes – in possession of similar regulatory capital – were approached for collaboration, in the end the prestigious THAI agreed to be main collaborator in the project around R-CPX. But agreements based on regulatory capital entail much uncertainty. As the ownership of regulatory capital is not openly exercised, and does not appear in contracts, the informal understandings of the agreement were not spelled out. And, as we shall see below, there is no guarantee that regulatory relations between countries will remain the same.

R-CPX: The Robotic Machine

R-CPX is a boxed-in space for the automation of cultivating cells and experimentation (See Figure 5.1). The robotic cell processor was central to the Japanese–Thai collaboration, but as a ‘science object’ it meant different things to them (Mol Reference Mol2002). To KHI it embodied the lucrative prospect of upscaling a slow and burdensome process of processing cells, which when shown to be safe and effective in therapy, would revolutionise the field of regenerative medicine; to THAI, its Good Laboratory Practice (GLP) status formed an immediate possibility to process cells and to conduct scientific experiments under internationally recognised conditions.

Figure 5.1 R-CPX.

(photo by the author, 25 June 2014)

The scientists working on R-CPX said that it promises a labour-extensive means of culturing cells on a large scale. At the time, the cultivation of cells used manual technologies at high cost and took weeks to months of highly skilled, dedicated labour. The quality of the hand-cultivated cells is uneven, and varies per institution, which influences the outcome of clinical trials. Automation is thought to improve precision and reproducibility, thereby enhancing the ability to comply to GLP standards, which are viewed as indispensable in the world of responsible and safe therapy provision (Williams et al. Reference Williams, Thomas, Hourd, Chandra and Ratcliffe2012; Soares et al. Reference Soares2014). Scientists compete in developing the robotics of automated and high-throughput cell culture systems. The Healthcare Engineering Group in Loughborough, UK, uses The Automation Partnership Biosystems (TAP Biosystems) for the cultivation of human embryonic stem cells and bone marrow-derived cells (Thomas et al. Reference Thomas, Chandra, Hourd and Williams2008), and KHI, Tokyo, has developed a robotic stem cell processing machine, R-CPX, using Auto-Culture®. Japanese scientists claimed TAP was less efficacious compared to Auto-Culture® (Kami et al. Reference Kami, Watakabe and Yamazaki-Inoue2013), which is advertised as uniquely capable of automatically replacing the culture medium, centrifuge cells, split cells and taking photographs for morphological assessment, as well as running according to Good Manufacturing Practice (GMP) standards.

As the cells are intended for clinical applications for a number of serious, intractable diseases and cosmetic applications, the quality of the cells is crucial. In regenerative medicine, where ‘the product is the process’ (Mason and Hoare Reference Mason and Hoare2007), just a slight difference in processing environment can lead to cell ossification. The question of upscaling is crucial to whether it is possible to manufacture consistently (Hargreaves Reference Hargreaves2019; Raymond and Williams Reference Rayment and Williams2010). And as the criteria for these mesenchymal stem cells (MSCs) are rather loose (see Chapter 4), it is difficult to check the influence of upscaling on the behavior of the cells (Michaels, 13/8/2014*). In short, although the adoption of the R-CPX machine promises an efficient environment for conducting clinical trials, scientific experimentation and the creation of medicinal products, there are wider concerns about the quality of the processed cells. These concerns are variously framed per regulatory system, and the views of scientists differ on the subject.

The Competing Interests Underlying Collaboration: Concerns among the Thai and Japan Teams

Through conversations with the collaborating scientists, I came to understand how the convergence of interests of parties can reproduce diverging interests among collaborative partners, leading to clashing expectations and prompting diverging actions. I identified four themes of concern on the basis of what scientists from both sides of the collaboration referred to as main incentives for working together: scientific results, medicine, trust and regulation. The divergent interests show how, under regulatory capitalism, regulatory capital forges together collaboration with competition.

Regulatory Contingencies

Although Japanese and Thai interests in the collaboration converged on prioritising scientific results, medicine, mutual trust and suitable regulation, the teams ascribed very different meanings to these terms. Where the Japan Team’s scientific interests prioritised regulatory permission and marketing licenses, the Thai team prioritised scientific expertise; where the Japan team believed in the immanent realisation of the promise of somatic stem cell therapy, the Thai team desired it but doubted its feasibility; where the Japan team saw trust in terms of regulatory lenience and mutual support for its scientific aims, the Thai team saw trust in terms of mutual support of scientific aims. The divergences of these perspectives all pointed to a clash between respective expectations about Thailand’s regulation of regenerative medicine.

Thailand’s regulation of regenerative medicine had been central to the initiative and negotiations of the Japanese–Thai collaboration. But as the value of Thai regulation as asset had not been made explicit, the terms of the collaboration were liable to change. For the Japan Team, Thai regulatory capital had been crucial to proving the worth of R-CPX. But as this expectation was a source of great reputational worry to the Thai Team, scientists were keen to emphasise that regulation in Thailand, although ‘strict’ already, needed to be improved and specified even further. While the Japan Team had planned to make strategic use of the regulatory discrepancy, the Thai expected a tightening of the regulation for regenerative medicine.

KHI obtained permission for the planned clinical trial for osteoarthritis, much later than expected. On 27 December 2016, KHI announced on its website ‘Cells Cultured by Automation Are Used for a World-first Clinical Study in Thailand’, for cell therapy of knee cartilage, using mesenchymal stem cells cultured by Auto-Culture® (Kawasaki 2016). But whether the resulting biological product will ever receive marketing permission remains unclear. An online R-CPX brochure indicates that KHI is still in the process of proving that the robotic machine is a superior tool: ‘For regenerative medicine and cell therapy using automatic cell processing system, the actual proof by clinical research is pursued’ (Kawasaki brochure, undated).

Since the start of the collaboration, both Thai and Japanese have been changing the direction of their regulatory boundary-work. Thailand revised its regulation in 2017 to build its regulatory capacity. The Thai Revised Drug Act, developed in concert with ASEAN, now requires a license for the manufacture and selling of drugs (including biologics) and pre-marketing electronic dossier registration. Advertising needs to be approved, and post-market requirements now include regular sampling, inspections and GMP clearance (Adcock Humhuan 2016; MOPH 2017; TFDA 2017). Further regulatory changes are still expected (Sombat, 27/6/2014). In the meantime, however, Japan’s regulation has become far more permissive and supportive since its regulatory overhaul of 2013 (Azuma Reference Azuma2015). There has been a flurry of offers from around the world to collaborate with Japanese enterprises, in the belief that Japan’s new regulation is permissive. It is Japan’s regulation that is now being used as regulatory capital, especially in relation to the clinical application of so-called MSCs (Sipp and Okano Reference Sipp and Okano2018). Regulatory change, then – more permissive in Japan, and stricter in Thailand – has reconfigured the lay of the regulatory land.

But what did this mean in terms of Thai–Japanese collaboration? In pursuit of the proof of the machine’s worth, the Japan Team continued to supervise clinical trials conducted by the Thai Team. And under the aegis of the Japan Team, the Thai Team continued to use R-CPX as a learning tool. But expectations were lowered as uncertainty around the marketing of therapy products created using R-CPX had decreased. The situation had made it more difficult for the Thai Team to address issues around the costs the Thai laboratory was facing. The R-CPX was useless without its software, and because the software updated regularly, the laboratory was presented with hefty bills. In addition, the import costs for assays and other instruments are extremely expensive for Thailand, as it trades under GATT rules (Sombat, 12/11/2014*).

The Thai Team, then, is facing the costs of its dependence on the Japan Team to continue using R-CPX. In addition, Thailand’s regulatory capital seems to have dwindled. In 2015, Japan’s government took it upon itself to invest into the harmonisation of Asian regulation for clinical trials in regenerative medicine and the marketing of therapies and medicinal devices (MoHWL 2015; PMDA 2017; FIRM 2018) such as R-CPX. No doubt the workshops and training seminars for multi-regional clinical trials Japan’s PMDA organises in Southeast Asia (PMDA 2018) will facilitate new forms of ‘collaboration’.

Regulatory Capital and Science Collaboration in Regulatory Capitalism

This chapter proposed the concept of ‘regulatory capital’ to shed light on the role of regulation in scientific international collaboration as illustrated by the case of the Japanese–Thai collaboration around R-CPX. The point of departure was the idea that regulatory discrepancies can stimulate particular forms of cross-border collaborations. Regulatory capital, as a relational concept, concerns the relations between potential collaborators. We saw how in the Thai–Japanese science collaborations regulatory capital was used to negotiate collaborative conditions. As the role of regulatory capital was not formally spelt out, there was uncertainty about the realisation of the core aims of the collaboration and ambiguity about the meanings of interactions and events, such as the opening ceremony of the collaboration. Thus, the Japan Team interpreted the installation of the robotic machine in THAI as a ‘donation’, while the Thai Team saw it as a lease and sometimes as an ‘expensive’ one at that.

An examination of the role of regulatory capital in the Japanese–Thai science collaboration shed light on the nature of regulation as an asset in negotiation. First, the relationality of the value of regulatory capital was realised not just in relation to the jurisdiction of the collaborative partners but also vis-à-vis the authority of significant others, such as the ISSCR, EMA and ASEAN. In the examined case, Thai regulatory capital increased after Thailand had announced ‘international’ regulation. At the same time, Thailand’s regulatory capital increased in negotiation with Japan, as its ‘international’ regulation was not viewed to be as problematic as Japan’s restrictive regulation. Second, the Japan Team did not read Thai regulation as forbidding but relied on its lack of detail and its flexible implementation. Flexible implementation of regulation, then, can increase the value of regulatory capital in international science collaboration but also its uncertainty. Third, the state may play an important role in cementing a collaboration. In Japan’s case, NEDO decided to circumvent the spirit of Japan’s own regulation, indirectly acknowledging the deficit of KHI’s regulatory capital; in the case of Thailand, the TFDA accepted the collaboration without guaranteeing the regulation authorisation needed to realise Japan’s ultimate aim of the collaborative project. Fourth, awareness of the value of regulatory capital can bring governments either to regulate (in case of Thailand) or to deregulate (in case of Japan) in order to enhance the country’s international position. Fifth, the relative nature of regulatory capital and its contingence on regulatory reform can increase uncertainty around a collaboration. Depending on how the collaboration is sustained and maintained, the expectations and the terms of the collaboration can be adjusted. Finally, the possession of other forms of capital (financial, scientific, medical, political) is crucial to whether a country can exercise its regulatory capital. In this case study, it was the awareness of both regulatory discrepancy and the capital inequality in other areas that made Japan approach Thailand for collaboration and for Thailand to accept.

This case study makes clear that, unlike idealistic views that define collaboration in terms of the pooling of efforts and resources to realise a common scientific goal, in the context of inequality, collaboration is often based on the fertile feeding ground of competing interests and aims. What the collaborative partners share is a broad direction of agreed research and other collaborative aims, some of which are shared by the collaborators more than others and some not at all. For instance, the transfer of expertise through the deposition of R-CPX was important to the Thai Team, while processing cells of a standard high enough to create therapeutic products tested by clinical trial was crucial to the Japan Team. As a consequence, the inauguration of the laboratory containing the robotic machine had diverging meanings for the Teams. Due to the competing aims of the partners, Thai regulation of regenerative medicine has also different significance. With their diverging scientific and material aims, the competing interest of the Teams in the regulation clashed. In this sense, we can speak of a fundamental interdependence of competition and collaboration. It is therefore not divergence but the convergence of interests that leads to conflicts about how to pursue them (Girard 1965; Demouchel Reference Demouchel2017).

As convergence in this case clearly connects unequal partners, partners had to tread carefully: trust and a positive atmosphere was crucial to the collaboration, expressed in the ritual inauguration of R-CPX. On the one hand, conflict avoidance was expressed in the preparedness to help and express friendship; on the other hand, the inexplicit role of regulatory capital and inequalities inherent to the collaboration encouraged a mutual understanding based on differences around control, surveillance, expertise, expenses, profit through these expressions of friendship and helpful attitudes. Conflict around finance, regulation and scientific aims was held at bay but continued to bubble under the surface. Thus, the Thai Team felt that they were paying too much for the use of R-CPX and were working on projects not entirely of their choice. On the other hand, the Japan Team, the dominant partner, saw its strategy backfire when instead of lenient, they were confronted by researchers bent on asserting their sense of what they considered acceptable scientific research by means of regulatory reform: by the time that KHI received the go-ahead for the clinical trial, Japan’s regulatory reform had already enable similar clinical trials at home (Cyranoski Reference Cyranoski2013; Azuma Reference Azuma2015; Sipp and Okano Reference Sipp and Okano2018).

In the R-CPX project, inequality proved to be both a source of conflict and of collaboration. But whether such inequality is aggravated, reproduced or diminished depends does not just on the circumstances of the collaborative partners; it is also contingent upon how interests are played out in the international dynamics of regulatory capitalism. Thus, in a situation in which the Thai Team was under pressure to help the Japan Team to lobby for regulatory permission, this would be in the interest of KHI but at the same time aggravate the global position of THAI scientists. In other words, by pleasing the Japan Team and maximising the benefits from the collaboration, this strategy could diminish the long-term regulatory fitness of the Thai elite science: its regulatory immunity would weaken. The notions of regulatory capital and regulatory tolerance can shed light on what it means to have a science collaboration under the global dynamics of regulatory capitalism. At the outset of Japanese–Thai collaboration, the Japan’s regulatory immune system was robust: it was known for its regulatory prohibition. In this situation, even research supported by NEDO, a Japanese ministry, could afford to be regulatorily tolerant: it financially supported a collaboration that violated the spirit of Japan’s regulation by seeking comfort abroad. For Thailand, however, as a developing nation, the acknowledgement of the role of regulatory capital in the collaboration would have been deeply damaging to its scientific ambitions, especially those of elite laboratories. For this reason, the Japan Team was wholeheartedly engaged in a struggle for a regulatory upgrade.

The use of regulatory capital in international science collaboration, then, is not just an indication of regulatory tolerance; it may also be an indication of ‘regulatory contagion’, that is, a collaboration that involves the local regulatory regime could be seen as infecting the reputation of the sciences in its jurisdiction. Elite laboratories need to avoid such infection at all costs, even when they are part of such collaboration. In terms of immunitary politics, the Thai Team felt that collaboration on ‘unethical’ science with its well-reputed Japanese partner was misrecognised symbolically in the ritual celebration of R-CPX. However, the collaboration with Japan in itself was hoped to make up for it and have a cathartic effect. This contrasts with the regulatory ‘pure’ country, Japan, which externalised its ‘unethical’ science with full support of the state. In Part III on ‘regulatory redemption’, I will elaborate on the link between immunitary politics and the ritualisation of regulation.