The Role of the State and the AJS

The prominent role of state governance in science, education and industry speaks for itself in Japan, known for its ‘iron triangle’ between government, bureaucrats and heavy industry (Johnson Reference Johnson1982). Since the introduction of the Japanese version of the Bayh-Dole Act in 1999, and the independence of Japanese universities in 2004 (Takenaka Reference Takenaka2005), academia is encouraged to forge collaborations with industry. Nevertheless, until the introduction of the PDA Act in 2014, it had been difficult to tempt heavy industry to invest in medical innovation (Umemura Reference Umemura2011). In the context of the US, however, Mirowski and Sent (Reference Mirowski, Sent, Mirowski and Sent2002) regard a clear separation between ‘pure’ science supported by the state and ‘applied’ science as supported by industry as an untenable ideology, rejecting the notion of scientists as self-interested and science as market-driven (Mirowski and Sent Reference Mirowski, Sent, Mirowski and Sent2002: 15, 23). But in the context of Japan, as we shall see, not taking into account this distinction would be unrealistic, as Japanese scientists observe major differences between ‘pure’ and ‘applied’ science and ‘state’- and ‘industry’-supported research settings. Although these separation-lines may seem artificial and subjective, the distinctions form an important point of orientation for scientists and policy-makers with very real social and financial consequences for the way science is organised and practiced. It is this distinction that allowed the Japanese state to guide the science markets according to its own redemptive vision: the AJS.

The AJS was first formulated as part of the Health and Pharmaceutical Promotion Strategy and the five-year Medical Innovation Programme (MEXT 2012), which were to address the problems of ageing society and economic slow-down through regulatory reforms and make firm industrial and political commitments in support of regenerative medicine. Apart from turning Japan into the world leader of pluripotency, the AJS would be relied upon to boost the export of new medical products and devices to the Asian market (Headquarters for Healthcare Policy 2014) The All Japan System (オールジャパン体制) envisaged ‘a system for All-Japan collaboration and co-ordination’ and refers to the collective efforts to set up a structure for the advancement of a system for iPSC research (JTS 2008) supported by MEXT and the Stem Cell and Regenerative Medicine Strategy Working Group. Former Cabinet Secretariat Toshihiko Hoshino, professor and assistant director of the Basic Technology Research Division (MEXT), was tasked with building an all-Japan promotion system in collaboration with related ministries and agencies and industry to support regenerative medicine using iPSCs originating in Japan (CiRA 2012).

The AJS was to form a bridge between basic research in academia and industry to create new applications coordinated through national centres and universities; and it centred on Shinya Yamanaka’s work on iPSCs. The AJS was led by Kyoto’s Centre for iPS-cell Research and Application (CiRA), headed by Yamanaka, who was made responsible for the improvement of iPSC lines and culture technologies, including assays. The AJS network was built on four All-Japan pillars of iPSC research, involving Kyoto University, represented by Shinya Yamanaka (CiRA), who was to oversee the creation of technologies for the development of safe and efficient iPSCs, the development of iPSC proliferation control and for the evaluation of clinical response; RIKEN, represented by Yoshiki Sasai, responsible for developing technologies for cultivating and determining the efficacy of multipotent stem cells, including iPSCs; Keio University, represented by Hideyuki Okano, responsible for developing iPSC treatment with a focus on the central nervous system; and, Tokyo University, represented by Hiro Nakauchi, responsible for developing iPSC lines and treatment centered on blood cells (see Figure 6.1). Importantly, AJS made CiRA central to the distribution of iPSC lines, intellectual property and the handling of research results, and it stipulated that the tentative regulation of the research network of AJS was based on common rules. These policies, as we shall see below, restructured the science both organisationally and substantively.

Figure 6.1

MEXT’s promotion system for iPSC research toward building an All-Japan system.

Courtesy from the Japan Science and Technology Agency, reference material, https://www.jst.go.jp/keytech/h20-1sanko.pdf (22/1/2024).

In the following extract from a CiRA Newsletter (CiRA 2012), Professor Toshihiko Hoshino describes the AJS as the redemptive force behind the regulatory overhaul:

A collective effort would mobilise resources in support of the long-term vision of iPSC cures.

The realisation of the AJS vision required overcoming institutional barriers to research promotion:

This plan made CiRA central to the iPS promotion strategy requiring other institutes to adjust, including scientific and ministerial ones, so as to realise the promise of iPSC research to society. Down-regulation was key to the realisation of AJS.

The re-brokering of Japan’s regulation radically affected regulatory developments internationally (see Chapter 8); but in this chapter, I focus how the regulatory reforms inspired by AJS affected Japan’s iPSC research community.

AJS and Collaboration

Scientists’ competing interpretations of AJS provide nuance to dominant views of the regulatory reforms and show how AJS was designed to misread what was actually going on. My conversations with scientists on All Japan collaboration at CiRA, iCeMS and CDB illustrate this. Takayama, an administrator from CiRA, Kyoto University, gave his view of AJS:

CiRA, an independent research institute, was one of the main beneficiaries of the life-science policy’s focus on iPSCs and regenerative medicine. It is supported by the Japan Science and Technology Agency (JST), which funds science and technology targets created by the Japanese government (JST 2021) and is a main financial backer of the AJS. Kawa, a researcher at iCeMS, Kyoto University, had a different view. ICeMS is supported by the World Premier International Research Centre Initiative (WPI), which was launched in 2007 by MEXT in a drive to build within Japan ‘globally visible research centres that boast a high research standard and an outstanding research environment’ (WPI 2020). Kawa said:

Kawa did not think that the AJS prioritised patients. He also emphasised the national focus of AJS. But the official version of the Health and Pharmaceutical Promotion Strategy had also announced collaboration with other Asian countries. Therefore, I asked about possible collaboration. Kawa said:

In Kawa’s interpretation of the Health and Pharmaceutical Promotion Strategy, Japan is hoping to export regenerative medicine products, while CiRA’s iPSC activities develop them in Japan. As scientists frequently pointed out, at CiRA one in thirty PIs was not Japanese (‘only one foreigner’), while iCeMS was required by its funder, WPI, to have 30 per cent foreign staff. But then, international collaboration is part of WPI’s mission statement. Asking about CiRA’s working relations with other institutions, such as the Medical School, Kawa responded:

As repeatedly confirmed, the Medical School regretted the concentration of funding on iPSC research and CiRA. The Medical School wanted the funding to go to more urgent research, judging it too early for clinical applications using iPSCs. In 2013, these diverging views made collaboration difficult. According to an experienced legal scholar from Kyoto, Abe, the Japan Medical Association was also reluctant to support clinical applications using iPSCs:

The term ‘regenerative therapy’ gained currency, including in government documents. The term, in his view, reflects anxiety about the clinical application using iPSCs – not just about whether it will work but also about its safety, even in the case of RPE, which is supposed to be relatively safe, due to the low number of iPS-RPE cells involved and their traceability in case the eye socket is pierced. Nevertheless, being the first in-human study, there was much apprehension about Takahashi Masayo’s iPS-RPE application.

The views above all pinpoint practices that have been mis-recognised by the AJS. First, the national focus on iPSC research as an all-Japanese iPSC production-line loses out of sight the plight of its poster-patients. Second, rather than a united effort of Japan’s best scientists, iPSC researchers were privileged by the JST and AMED. Third, rather than the collaboration with Asian countries, the AJS-policy strategised to export therapy products to lift itself out of its long-term economic slump. Fourth, rather than unity among iPS experts, many preferred independence, and some paved their own way to collaborate with overseas researchers. In addition, the will to successfully innovate was translated into regulation that presumed a form of therapeutic efficacy not recognised by the medical community. In other words, critical observers recognised the AJS’s misrecognition of what was going on in practice.

Friction in the Coordination of iPSC Research

Apart from misreading its collaborative dimension, AJS misread the smoothness of iPSC research coordination and the workload of scientists. As illustrated below, although the AJS enabled iPSC research through regulation and funding, the very coordinative functions assigned to CiRA also had disabling effects. For instance, the AJS encouraged the use and development of ‘Japanese’ standards through CiRA’s leadership. Most work on iPSCs involved collaboration with CiRA, and requesting iPSC-lines from its stock entailed the use of CiRA’s standards and methods, because ‘CiRA takes responsibility for the genome analysis involved and the user research centre for the tumorogenicity studies’ (Azuma and Yamanaka Reference Azuma and Yamanaka2016: 37). Thus, if a research centre derives iPSCs from sources other than CiRA for therapeutic use, the centre in question and CiRA would also have to characterise and analyse the differentiated cells together. Established researchers expressed frustration with the dependence involved in this ‘collaborative’ arrangement.

The examples that follow concern the research practice around the first clinical iPSC application in humans with AMD and the centrality of CIRA’s strategy regarding the global standardisation of its methods. The clinical application took place at RIKEN-CDB, Porto Island, in Kobe, in collaboration with the Foundation for Biomedical Research and Innovation (FBRI) – next door – and CiRA at Kyoto University. Masayo Takahashi, the PI of this clinical application of iPS-RPE, had moved from the University of Kyoto, as she found its Medical School’s ‘conservative attitude’ to iPSC applications disagreeable. According to a researcher on the project, she was happy about the regulatory reforms that had been formally announced:

A great step forward, the researcher explained, is that the RM Act facilitates the outsourcing of cell processing:

Using a company seems to take pressure away from the PI. But as collaboration with a company introduces new possibilities, other pressures appear, as we shall see below. Of immediate importance to the pilot study was the availability of a Cell Processing Centre (CPC) at IBRI. Collaborating with CiRA, Takahashi uses Yamanaka’s assays to test the autologous (from the patient) iPSC–derived neuron stem cells to generate RPE. A ‘scientific mediator’, who mediates between scientists on regulatory and coordinative issues, explains the centrality of CiRA in their work:

This collaboration was crucial to the AJS vision, as it was widely thought that the first successful iPSC applications would become a global standard. The same mediator explained:

In the context of AJS, the first successful in-human application of iPS would have had to make use of ‘the Yamanaka assay’. But the development of assays is part of a long-term process of trial and error and something that scientists find important to experiment with. Without having a say in the use of assays, Kimura, a decision-maker in FBRI, where the clinical application takes place, commented that FBRI could not be held accountable for the iPS pilot-study (Kimura, 7/11/2013*). The translational researcher in charge, Hashigawa, further clarified this stance in relation to how CiRA frequently changed protocols:

This researcher summarised the AJS as ‘A bad idea, promoted by the bureaucracy’. ‘The power of Yamanaka and Takahashi’, in his view, ‘should be limited to their own field’, that is, basic research. This researcher was clearly upset about ‘having to use Yamanaka assays and feeders [when testing patients], just because these have to become world standard’ (Hashigawa 1/11/2013*).

The symbolic violence with which the AJS created a Yamanaka-discourse and a Yamanaka personality-cult in the media also seemed to transcend the wish of Yamanaka himself. In fact, Yamanaka had tried to resist the media-rituals and bureaucracy that had turned him into ‘Mr iPS’. Hiroshima, a vice-president of Academia Japan, the company that licenses and brands CiRA/Yamanaka products, explained that it is the mission of Academia Japan to advertise and turn Japanese iPS into a global success. The wide use of ‘Yamanaka assays’, ‘Yamanaka cell lines’ and ‘Yamanaka methods’, he related, was crucial to the company. Hiroshima laments:

These comments illustrate some of the frustrations generated by the conflicting demands of scientists and managers under the political requirements of the AJS.

The AJS spirit behind the regulatory reforms had been able to facilitate iPSC research applications but not without creating frictions through the coordination requirements that are part of its All-Japan vision. International collaboration is to serve All-Japan, while All-Japan coordination means a hierarchic leadership headed by CiRA. AJS caused frustration: Academia Japan found marketing ‘Yamanaka’ brands hard; scientists disliked having to use assays just because they are to be patented by Academia Japan; medical institutions did not want to take responsibility for applying assays; and, the world was not waiting for Yamanaka iPSC lines and assays.

Scientists’ Options and Considerations When Planning Clinical Applications

As well as being framed by the AJS, the regulatory reforms were aimed at encouraging the commercialisation of regenerative medicine through the industry pathway for clinical trials using iPS and methods from the CiRA. The iPSC bank at CiRA provides cell-lines for industrial research (in accord with Good Gene, Cell and Tissue Practice, GCTP) and company sponsored clinical trials (PMDA 2021). Even though some researchers prefer doing clinical research using their own processed cells through the RM Act first, the research pathway, the AJS vision favoured working on clinical trials with the financial backing of companies through the industrial, PMD pathway, oriented to the marketing of regenerative therapies. The RM Act regulates the use in research or in medical procedures of unapproved regenerative medicine products in medical institutions. It has lower integrity standards compared to those of the PMD Act pathway. For instance, clinical research does not require GLP – only GMP-like conditions – and resultant data do not count towards clinical trial approval under the PMD Act (Azuma Reference Azuma2015). The RM Act pathway is also considered cheaper, though this may depend on MoHWL requirements for a particular application (Azuma Reference Azuma2015; Azuma and Yamanaka Reference Azuma and Yamanaka2016). The examples below illustrate how the introduction of regulatory measures supported by the AJS has shifted conditions for conducting clinical trials in such a way that they encourage making use of CiRA’s iPSC bank, collaboration with industry and an orientation on marketing rather than on scientific research.

Constraints on the Conventions of the Science Community

Research leaders in main iPS-hubs, though aware of its benefits, expressed doubt that the vision of AJS was conducive to conducting basic science; they were acutely aware of rebellion against CiRA’s central role in iPSC research and its standard-setting role. In particular, there was anxiety about the expected commercialisation of regenerative medicine and its distraction from basic science. Although working with industry may provide the funding and conditions for marketing to scientists working on regenerative therapies, such collaborations play havoc with ‘traditional’ modes of scientific research among academic colleagues.

The intense negotiations and skills involved in the acquisition of resources, the application for funding, permissions and certificates, maintaining relations with CiRA and accommodating the visits of audits and collaboration with hospitals take up much of a PI’s time and can be nerve-wracking. Many iPS scientists prefer to leave such pressures to company CEOs if they can. Nevertheless, being tied to a company places constraints on the conventional activities of the scientific community. One scientist involved in an iPSC application, Kishi, explains:

Collaboration with companies encourages secrecy and hampers scientific exchanges. When I met scientist Sumida, who uses iPS reprogramming to create cardiomyocytes at Keio University, I asked him why he did not collaborate with another scientist, who engaged in very similar research. He said:

This scientist does not use CiRA’s iPC reprogramming methods, both because he is tied to a patent used by the company he works with but also because in his view his vectors are better:

As such integration could lead to tumourisation, Fukuda does not see any reason to give up the Sendai vector. In fact, he prides himself of spending only twenty-five days on reprogramming and differentiation – ‘much faster than other methods’. When asked, Fukuda said he would also use the Sendai vector for clinical applications. But others who work with CiRA, such as Yanagishi from an Osaka-based research group that used CiRA iPSC lines to differentiate into cardiomyocytes, claim that the episomal plasmid is much better (Yanagishi, 3/12/2013*).

A number of researchers have experienced ‘suffocating influence’ through the AJS. Kishi aims to use iPS reprogramming to generate HLA- (human leukocyte antigens) and HPA- (human platelet antigens) controlled platelets for allogeneic transfusion. Kishi was diversifying his regulatory pathways for strategic reasons. He had begun preparations for a pilot-study at CiRA:

Kishi planned to make platelets using his own assays: ‘You do not need to test for gen- mutations: we can use irradiation to eradicate any contamination.’ This allowed him to work relatively independently. So, Kishi was going to use three different protocols for cell processing: one for a clinical pilot-study with KUH to produce platelets in the laboratory under GMP-like conditions, one for the generation of iPSCs with a specific HLA of GMP-grade cells for clinical investigation following the RM Act and one for large-scale production of GMP-grade platelets for industrial use with Megacaryon and Toray using the PDA Act. The combination of managerial and scientific work involved Kishi found taxing:

Apart from experiencing organisational difficulties, Kishi was also frustrated with AJS for what he regarded as ethical reasons: ‘Despite the low level of blood donation in Japan, Japan does not support the production of platelets: they believe that it is a social problem.’ Thinking that the US does not have these issues, Kishi was wondering whether to go for clinical trials in Japan or in the US. Europe was not an option, he reflected: it has good systems for blood donation.

The AJS-vision introduced new constraints and dilemmas in the work of scientists. First, scientists were pitted against one another insofar as they are encouraged to work with companies: competition between companies hampers scientific exchanges on research methods and academic collaboration. Second, the pressure to work with CiRA created dilemmas: some scientists used their own vectors for reprogramming, because they worked in their research or because they had commercial contracts that require their use. Third, scientists missed chances to experiment with assays and to develop their own theories about suitable standards. And fourth, increased competition and pressure to commercialise has pushed scientists to adjust their research designs and to collaborate with industry. In short, researchers’ attention to patient needs and scientific quality had shifted towards regulatory options and marketing.

Working with and around AJS Politics

The financial resources, responsibility and authority that came with research funding made CiRA vulnerable to critique and conflict about funding, priorities and methods. New modes of working affected the science itself.

Researchers have moved away from CiRA to other institutes for various reasons as a direct or indirect result of the implementation of the AJS-vision. Some objected to the hierarchic organisational structure at CiRA, rejecting political interference. Immunologist Shirai, who moved to Kobe, wanted to collaborate internationally in iPSC applications to counteract forms of cancer. Shirai explained why he left CiRA:

The ISCBI aims at the global harmonisation of quality control, safety and efficacy of human pluripotent stem cell banks and their derivative cell therapy products. Shirai believed that CiRA was only interested in setting Japan’s standards for the world to follow. His new institutional environment, by contrast, encouraged participation in this international initiative as it favours ‘real’ international collaboration.

Many researchers are disturbed by the focus on iPSC translation. For instance, one researcher of autologous iPS-derived MSCs for muscular skeletal conditions in, for instance, multiple sclerosis and rheumatism, concluded that the method does not offer prospects to patients over the age of thirty-eight. For this reason, he moved to another research centre to concentrate on physical rehabilitation. This, he believed, would be crucial to the success of any cell therapy for muscular skeletal disorders (Hameda 28/3/2013*). Other researchers, such as Nakatsuji Norio, openly argued that a focus on iPS drug-screening is the most viable use of iPS methods, but he preferred to use less costly methods from biochemistry to emulate cell functions using biomaterials and tissue engineering (Nakatsuji Reference Nakatstuji2015: 101). Tissue engineers, such as Tanida from IFMS, felt they were passed by unwisely: ‘You need scaffolds to get the cells to work.’ Tanida had developed a sponge to deliver growth factors to the affected tissue. Like other leading tissue engineers, such as Okano and Iwata from Tokyo, Tanida said, tissue engineers have lost out to medical professionals that translate iPSC research too early:

Tanida decided to work on iPSCs to get funding that would also support his research. But he felt uncomfortable doing so, as his main expertise is making the cells work through scaffolds. He explained that ‘assays and vectors are predetermined’, criticising government policies and the Forum for Innovative Regenerative Medicine (FIRM) for mainly investing in large companies that will take the industry abroad to make profit. Other researchers echo this critique. Although Tanida supported a policy that encourages collaboration with industry, the AJS neglects small specialised companies even though ‘you need them for ideas to create devices useful for both the lab and the science’ (Tanida, 15/11/2013*).

Some researchers criticised AJS for the practical consequences of its emphasis on using the same vectors and assays, while others were more worried about scientific classifications of pluripotency and international banking standards. Cell biologists pointed out that science is universal and requires universal standards for measuring pluritpotency across the fields of hESCs and iPSCs (see also Nishikawa, Goldstein and Nierras Reference Nishikawa, Goldstein and Nierras2008). Fierce supporters of this stance were leading researchers of hESCs. One expert lamented the ethical halo of iPSC research:

Until iPSC research became the focus of attention, hESC-research had slumped, due to strict regulation and ethical issues of oocyte donation (Slingby et al. Reference Slingby, Nagao and Akabayashi2004). A leader in hESC-research and regulation commented that policy-makers decided rather late that encouraging hESC-research would support the iPS venture (Umeda, 27/2/2016*). Another leader of hESC-research criticised CiRA’s iPSC bank as a waste of money and efforts, because allogeneic applications still require immune suppressants. Instead, he recommended emulating Pfizer’s example:

Many scientists were in favour of conducting hESC research but did not think Japan’s regulatory climate made it viable.

Another reason for opposing AJS related to the need for international industrial standards for production. Hashigawa, from Kobe’s FBRI, did not just work on clinical applications of iPS research but also on those of MSCs, T-cells and gene therapy. He worked in both laboratory and clinic and acted as business consultant on international standardisation. Hashigawa said that he could not find international collaborative partners in Japan due to the national focus of the AJS. This is why Hashigawa and his team had started to work on new industrial standards in the context of the International Alliance for Biological Standardization (IABS) (cf. Abbot et al. Reference Abbot, Agbanyo, Ahlfors, Baghbaderani and Bartido2018) and the ISCBI. He compared it to ICH-guidelines for good clinical practice in the pharmaceutical industry, providing guidelines for GMP and risk-management in regenerative medicine:

In the meantime, PMDA leaders had also realised that the internationalisation of regenerative therapy necessitates the creation of such a system. But there are researchers who object to the hijacking of Japanese science through companies that move abroad. One research-leader, for instance, fiercely opposed the collaboration of Takahashi Masayo with Healios, believing its establishment of a branch in the US was an omen of selling out iPS to the US (Yamaguchi, 14/11/2013*). Other researchers, however, claimed that a nationalist emphasis on the Japaneseness of iPS had set the scene for the scandal around STAP (Stimulus-triggered acquisition of pluripotency)-cells at RIKEN-CDB (Tsuji, 05/2/2016*; Takehara, 26/2/2016*), which involved the attempt to create pluripotent stem cells by applying stress to ordinary cells (Cyranoski Reference Cyranoski2014). For a few weeks, STAP-cells shook the world, as it was thought that they were even easier and quicker to produce than iPSCs (Suda Reference Suda2015). Its dismantling left RIKEN-CDB considerably weakened (Normile Reference Normile2015). In fact, the STAP scandal resulted in the closure of the CDB (Osaka, 27/1/2016*) and its and reassignment of many of its former labs into a new institute, the Centre for Biosystems Dynamics Research.

The AJS has made iPSC research central to Japan’s quest for ‘regenerative therapies’. Funding and infrastructure support emphasised iPS over other branches of science such as tissue engineering and hESR. AJS’ encouragement of collaboration with industry took resources away from basic research and hampered collaboration with small specialised companies. Many researchers used the AJS-vision as an opportunity, but others viewed it as a hindrance. Of the latter, many grudgingly adjusted their research focus and methods, but others moved to different fields. There was conflict especially around the focus on Japan. Some researchers advocated for CiRA’s international leading role, while others emphasised the importance of more fundamental collaboration in industrial and scientific standard setting, while again others criticised AJS for making iPSC research vulnerable to profiteering companies that go abroad.