In 2007, a Japanese scientist named Shinya Yamanaka and his laboratory members succeeded in creating an artificial stem cell, called an iPS (induced pluripotent stem) cell (Takahashi et al. 2007). The group found that adult human cells can be reverted back to their stem cell states by introducing a few gene reprogramming factors.1 Similar to embryonic stem cells, iPS cells have the genetic potentiality to become any kind of cell in the human body. Because of this capability—known as pluripotency—iPS cells are now considered a powerful scientific resource, particularly for use in exploring various stem cell mechanisms, disease modeling, drug discovery, and so forth. They are also considered likely to have a huge market for therapeutic applications.
IPS cells have rapidly spread into various laboratories all over the world and have opened up new fields. While many countries support stem cell research in various ways, the Japanese government has been especially supportive of such efforts following the initial discovery of iPS by Yamanaka, who was heralded as a national hero. After Yamanaka received the Noble Prize in 2012 for his work on iPS cells, the government swiftly and radically transformed its national science policy to support iPS cell research, medicalization, and industrialization (Mikami 2014; Sleeboom-Faulkner et al. 2016). In particular, the government has focused its sights on creating new therapies in the field of regenerative medicine. To advance these goals, the Japanese government not only has provided considerable funding to institutions conducting research using iPS cells for regenerative medicine, but has smoothly modified previously strict regulations around the use of cells to accelerate these efforts. Sociologist Koichi Mikami (2014) refers to this arrangement as ‘state-supported science’, where the government has made the advancement of regenerative medicine into a national project in order to ‘win’ against global competitors and increase economic growth.2 The stem cell laboratory in Japan where I conducted my fieldwork,3 the Murakami laboratory,4 is a leading laboratory within this national project. This article focuses on how the birth of iPS cells not only changed relations within this laboratory, but initiated a broader societal transformation as well.
At the Murakami laboratory, scientists were working on creating parts of eyes by manipulating iPS cells to treat eye diseases. However, the scientists have faced a lot of challenges in this work, in large part because of the iPS cells themselves. All living beings require proper care to thrive, but most cell lines and experimental animals used in laboratory settings have been genetically modified and standardized, so their care is fairly predictable. By contrast, iPS cells are very mercurial and elusive: they can die unexpectedly or differentiate into strange cells. Living in a petri dish in a laboratory, they are easily affected by their environment—the shape of the dishes, the growth medium and other chemicals used, and the handling style of technicians all matter. Here, I highlight this sensitive, unstable nature of iPS cells, which makes them what I call ‘highly relational objects’. Not only are the cells hard to keep alive in the laboratory, but the Murakami laboratory quickly found that their uncommon character did not fit into the pre-existing legal and regulatory systems in Japan governing the safe use of medical technologies.
Despite these challenges, laboratory members have found ways to manipulate and culture the cells to use them for experimental and therapeutic purposes. For one thing, they have learned to use the cells’ sensitivity and relationality to their advantage. After being extracted from living bodies, cells cannot survive without the proper artificial environment that mimics a body. As I have argued elsewhere (Suzuki 2015), such intervention in the lives of these cells is made possible through the routine use of tools, such as petri dishes, microscopes, and chemicals, but also through embodied knowledge and attentive care that goes beyond what is expected of most technicians and laboratory members in similar settings. Keeping the iPS cells’ pluripotency intact and being able to differentiate them into the desired types of cells needed for experiments requires skill and experience. Highly trained technicians are able to notice subtle differences and respond to cells accordingly. Cells, in turn, respond to human intervention. At a regulatory level as well, scientific institutions and governments have had to adapt to iPS cells. As we will see, the Murakami laboratory has had to negotiate with Japanese authorities to come up with new legal frameworks to govern the use of these cells for medical purposes. As a result, the national laws and regulations—previously based on two categories, ‘drugs’ (pharmaceuticals) and ‘medical devices’—have been expanded to include living cells.
To shed light on these various mediations, in this article I elaborate on the concept of the ‘ecological trap’, which the anthropologist Alberto Corsín Jiménez (2018) uses as a heuristic notion to help explain interspecies relationships. Corsín Jiménez and his colleague Chloe Nahum-Claudel (2019: 393) argue that traps are “material entanglements of lives, designs for complex and fraught relationships across the boundaries of the human and the nonhuman.” Inspired by their discussion, this article explores how scientists and technicians at the Murakami laboratory attempt to capture the potentiality of stem cells by carefully arranging their immediate and broader environments. In the context of regenerative medicine, capturing these cells entails investigating the cells scientifically; training technicians and designing a proper facility to carefully culture cells for use in experimental surgery; and negotiating with regulatory authorities to bring new medical solutions to market. The heterogeneous arrangement for trapping iPS cells—including the cell microenvironment, the laboratory infrastructure, and wider regulatory systems—is key to realizing the ultimate goal of creating regenerative medical interventions.
By elaborating the concept of the ecological trap, this article aims to rethink what is taken for granted in science and technology studies (STS) discussions about biotechnology, in particular what Stefan Helmreich (2008) calls ‘species of biocapital’. In these discussions, inspired by Michel Foucault's concept of ‘biopolitics’, scholars theorize the contemporary joining of biotechnology and capitalism primarily as a unilateral flow toward increasing alienation among individuals and the commodification of living bodies (e.g., Rajan 2006; Rose 2006). Within this flow, Catherine Waldby (2002) argues that life itself is becoming more fragmented and that ‘biovalue’ is being harnessed under the logics of biopolitics. According to Waldby, “rapid developments in biotechnology have produced more and more kinds of bodily fragments, that can be alienated, altered, redistributed and reincorporated in increasingly complex economies” (ibid.: 309). Importantly, the production of these fragments takes place “not at the level of the body as a macro-anatomical system but at the level of the cellular or molecular fragment” (ibid.: 310).
The commercialization of the life sciences, in this sense, has nourished the ambition to manipulate the fundamental building blocks—cells and molecules—of life. Correspondingly, there is a tendency among scientists and STS scholars to objectify those building blocks. Ethnographic research in actual laboratories, however, shows that the manipulation of iPS cells is far from straightforward. This is because the cells push back against efforts to control and manipulate them: they are not just passive fragments for humans to act on. By resisting unilateral standardization and commercialization, iPS cells have forced humans to adapt and transform their behaviors and governing systems to accommodate the cells. In addition, these transformations are taking place not only in laboratories but in complex assemblages of institutions and governing bodies.
Anthropologists of science and STS scholars have conducted extensive research on stem cell research and its applications, including, for instance, ethnographic studies of laboratories and infertility clinics as well as comparative studies of governing regulations and ethical controversies related to stem cells (e.g., Bharadwaj 2012).5 To explore the agency of cells and the mutual adaptation in institutional assemblages, I turn to feminist STS work on the study of care in technoscience. Mianna Meskus (2018), in particular, provides a useful jumping-off point. Based on her fieldwork at an iPS cell research laboratory in Finland, Meskus points out the importance of care and what she calls ‘craftwork’ in stem cell technology, which is often overlooked in the face of increasing standardization or commercialization. Since cells are living beings and iPS cells are especially elusive, they require a certain kind of specialized, attentive labor that goes against the trend toward automation of cell culturing and large-scale ‘biobanking’. I extend this argument further by focusing on the slippery and uncertain agency specific to iPS cells. My research suggests that iPS cells are not easily embedded in existing institutions or regulations as a standardized ‘tool’. Rather, as I will show, their elusiveness and powerful pluripotency force the transformation of laboratory arrangements, procedures, and even national regulations and laws.
Methodologically speaking, this requires what the anthropologist Ayo Wahlberg (2018) calls ‘assemblage ethnography’. Rather than focusing on a single laboratory study (e.g., Latour and Woolgar 1986) or relying on a multi-sited ethnography (Marcus 1995), the assemblage ethnographic method follows “the configurations … found within certain assemblages, complexes, or apparatuses” (Wahlberg 2018: 8). As such, I start from the Murakami laboratory's cell culturing room, then move along different scales to follow the laboratory arrangements, regulations, and laws that, taken together, configure the trap for capturing the potentiality of iPS cells.
My central argument is that the mutual care applied in the assemblages of iPS research in Japan is best understood within the framework of an ecological trap. To spell out this argument in some detail, I first refine Corsín Jiménez's original iteration of the concept. The core sections of this article apply this concept to the Murakami laboratory's nested structure of the trap for iPS cells: cells live in a dish (their immediate physical environment) and are situated within a highly managed environment called the Cell Processing Center. The same ‘trap structure’ also applies to the wider institutional assemblages of which the laboratories are part. Most importantly, the ecological trap captures the co-mediation between humans and cells. When humans try to manipulate and capture the potentiality of stem cells for medical and industrial applications, they also, conversely, find themselves being captured by cells.
Making an Ecological Trap for Cells
This section departs from conventional ethnographic understandings of hunters and traps by narrowing in on the concept of the ecological trap. Classic discussions of traps in anthropology have tended to focus on the efficiency of humans using traps to capture fish, animals, and birds for food and medicinal purposes, in contrast to the activity of hunting (e.g., Morgan 1868). More recently, some STS scholars and anthropologists have started to pay attention to traps once again. These scholars focus on how the interspecies interactions between hunters and their prey are built in the shape and form of traps (Corsín Jiménez 2018; Corsín Jiménez and Nahum-Claudel 2019; Gell 1996).
In these discussions of traps and entrapment, anthropologists often take it for granted that humans know their prey very well (Gell 1996; Ingold 2004). For example, Alfred Gell (1996) argues that not only do humans know who their prey are, but they also know their prey's behaviors and habitual responses. Gell emphasizes how traps give material form to hunters’ knowledge of animal prey. He writes that “once the trap is in being, the hunter's skill and knowledge are truly located in the trap, in objectified form, otherwise the trap would not work” (ibid.: 27). For that reason, he notes, “traps can be regarded as texts on animal behavior” (ibid.). Putting it differently and borrowing a concept from the biologist Jakob von Uexküll ([1934] 2010), Gell (1996: 27) states: “Traps are lethal parodies of the animal's Umwelt.” In other words, according to Gell, traps are created to mimic and encompass the animal's world—bodies, behaviors, and surroundings. However, I found while doing fieldwork that stem cell scientists do not always know what they are trapping. In addition, they have difficulty mimicking cells’ surroundings. The case of iPS cells, an emerging biotechnology, thus raises a key question: how can a trap be arranged when hunters do not know much about their prey?
Corsín Jiménez and Nahum-Claudel (2019) offer a unique understanding of a trap that I build upon here. They argue that a trap should be understood less as an embodiment of complete knowledge of one's prey and more as a modality of interspecies relationality built on partial knowledge of the other. In their words, a trap “is a complex architecture of gradations where bodies and landscapes and nonhuman persons move and orient their capacities towards one another in an uncertain game of alignments. The architecture of these inclinations and complicities, these unstable dispositions, surfaces as a process of entrapment” (ibid.: 393). In an earlier experimental essay, Corsín Jiménez (2018) focuses on the spiderweb, among various kinds of traps such as leg-holds and snares. While his use of the spiderweb is mostly metaphorical and abstract, the material flexibility of spiderwebs offers a compelling way to think about what goes into trapping iPS cells.
Spiders make webs on and between twigs, leaves, and fences while considering aspects of their environment, such as wind and sunlight. According to scientist Shigeyoshi Osaki (2015), who specializes in the biopolymers in spiderwebs, spider threads are outstanding because they are not only strong but also flexible and soft. Spiders spend hours creating complex structures with several types of thread for the warp and weft. Using these flexible threads, they are able to make a variety of sizes, shapes, and structures. But once the web is completed, rain or wind could break it. Or, after a spiderweb catches an insect, the insect may resist and escape from the adhesive web. Thus, spiders need to continuously mend the web when it breaks. Spiders collect broken webs and eat them to reuse threads, maintaining the web attentively over time.
Similarly, iPS cell scientists and technicians create a trap for cells that consists of a complex and changing mixture of scientific equipment, infrastructures, institutions, and regulations. Since the cells are very elusive, the scientists and technicians must continuously rearrange and rebuild the threads of the trap. In understanding how these processes work in scientific settings, historian of science Hans-Jörg Rheinberger's (1997) insightful discussion comparing the experimental process to spiderwebs is helpful. He argues that unknown scientific objects—what he calls ‘epistemic things’—emerge through the arrangement of the experimental setting, or ‘experimental systems’. These experimental systems include tools, laboratory organizations, scientific communities, and institutional settings. Interestingly, Rheinberger also uses the metaphor of the spiderweb to explain the relation between an experimental setting and its epistemic things (ibid.: 78):
They [experimental systems] constitute a kind of experimental spider's web: the web must be meshed in such a way that unknown and unexpected prey is likely to be caught. The web must “see” what the spider actually is unable to foresee with its unaided senses. But the web must not become too rigid. In deliberating upon the manner in which a system is to be handled so as to let the unknown intrude and invade it, Max Delbrück has spoken of a “principle of measured sloppiness.”
Rheinberger argues that the spiderweb should be relatively loose in order to capture unknown prey—that is, new scientific objects or techniques. Spiderwebs as such embody an entanglement between different species, and might be described as ecological traps. This understanding helps to explain how heterogeneous things such as dishes, chemicals, infrastructures, and regulatory systems are organized flexibly to capture unknown and highly relational iPS cells.
Another example, provided by Corsín Jiménez (2018), is that of an experimental hut used for research in Tanzania, where entomologists monitor the flight patterns of malaria-inducing mosquitoes (see Kelly 2011). Designed as a mosquito trap, the hut is at the same time an ecology where mosquitoes, local villagers, and scientists share an environment. Similarly, as I will show, the trap for cells at the Murakami lab is an environment shared by lab technicians and scientists and, in this way, is a part of human society. Put differently, the ecological trap for cells was created by human society, but the trap has also transformed human society little by little. Ultimately, humans are not only trapping cells to exploit their potentiality for medical purposes; at the same time, they are transforming society for co-habituation with cells.
In sum, by using the concept of the ecological trap, I aim to highlight how the materiality of iPS cells as highly relational objects requires a loose and flexible set of arrangements to capture them. IPS cells cannot respond to rigid structures or quick changes. Rather, they transform slowly, affected by their surroundings and human care. In the process, what iPS cells are or what they can be used for gradually becomes stabilized through the arrangement of the ecological trap. This ontological question about the nature of the cells—what they are—is still an open one for researchers and regulators. Within the framework of translational research in the field of regenerative medicine, cells are understood as technical tools to be transplanted into human bodies, after being cultured for a certain period of time. At the same time, iPS cells are novel scientific objects that scientists are still exploring to understand their mechanisms and epigenetics. In addition to being scientific objects and technical tools, iPS cells are also living beings. Their characters and morphologies change all the time. This multiplicity requires a certain kind of looseness and flexibility, which the examples of the spiderweb and the mosquito hut help to articulate. In showing how the ecological trap is co-created with iPS cells themselves, this case sheds light on the co-production of cells and human society and emphasizes processual relationality over ontologically predetermined relationships.6
Context of the Laboratory and Its Clinical Study
Before I delve into the ethnographic material at hand, it is important to understand the broader context of the laboratory and its clinical studies. The Murakami laboratory where I conducted research was led by a clinician-scientist named Yoko Murakami. The laboratory belonged to a world-famous life science institution in the western part of Japan. As an ophthalmologist, Murakami aimed to cure retinal diseases by combining stem cell science, genetics, and regenerative medicine. Taking on this challenge of bringing technologies from the bench to the bedside promptly was key to her vision of translational research. Here, I focus on her efforts to replace damaged RPE (retinal pigment epithelium) with cultured RPE derived from iPS cells (RPE-iPS cells) to cure age-related macular degeneration (AMD).
As mentioned earlier, soon after the Yamanaka group had created human iPS cells in 2007, the Japanese government turned its support of iPS cell research and regenerative medicine into a national project. Murakami became a key player within it because she was preparing to transplant cells derived from iPS cells into the world's first human patient. Among the various parts of the human body, the eye became the first organ for the application of iPS cells because RPE-iPS cells consist of small numbers of cells that are relatively easy to culture in a dish. Early on in the process, Murakami recognized clearly that the scope of her translational research would involve not only scientific experiments and biotechnological developments but also social transformations, including educating the public and changing regulatory and legal frameworks, as I discuss later.
In the basic flow of translational research, scientists first conduct experiments on animals, followed by experiments on humans. In Japan, one of the possible tracks toward human experiments is a physician-led clinical study, in which a physician tests a new medicine or technology on a few patients. To get approval, the physician submits a relatively small-scale plan to the Ministry of Health, Labour and Welfare (MHLW), the regulatory body in charge. The second track is a company-led clinical trial, in which a company (from the pharmaceutical, medical technology, or tissue engineering industry) tries to ensure the safety and efficiency of a new treatment by testing it on several hundred patients. In this case, the Pharmaceuticals and Medical Devices Agency (PMDA)—a national agency under the MHLW, similar to the US Food and Drug Administration—examines the data and plan. After PMDA has checked these, then, finally, the MHLW approves. A company-led clinical trial is more difficult to get approved because it requires detailed strategies, accurate data, and a considerable number of patients. It also requires a large budget from the sponsoring company since the trial is conducted over a long period.
At the time of my fieldwork in 2013–2014, Murakami had already accumulated data from animal experiments and was preparing for the first physician-led clinical study. Her laboratory was also undertaking collaborations with venture capital companies and pharmaceutical companies in order to conduct a clinical trial in the near future.7 In 2014, Murakami succeeded in transplanting RPE-iPS cells into a patient as a part of her lab's physician-led clinical study. It was the world's first transplantation of cells derived from iPS cells. The following sections depict how Murakami and her collaborators went about meeting their goal of the industrialization of iPS cells by arranging heterogeneous elements to make an ecological trap for the capture of the cells.
Tinkering with the Cell Microenvironment
For biologists, it has been challenging to make a proper environment for cells to survive outside of living organisms. Since observing cells in a body is difficult, cell biologists have historically opted to mimic and tinker with cells’ environments so that they can observe them in a dish. Stem cell scientists and tissue engineering scientists, as specialists of stem cells, have further explored how the differentiation of cells is regulated by feedback from their environment, which includes various cells, biological agents, and molecules (Watt and Hogan 2000). Through the comparison of in vivo and in vitro experiments, scientists have learned about the maintenance of stem cells and techniques to differentiate and reprogram cells in a dish. In this section I discuss how scientists explain the relation between the cells and their environment, as well as how they intervene in cells on this basis. I also delineate how those concepts were embedded in the practices of the Murakami laboratory specifically.
Inspired by ecologists, some stem cell scientists use the term ‘cell microenvironment’ to explain the mechanisms of cellular interactions. Stem cell scientists suggest that the “cell microenvironment is constituted by factors that directly affect conditions around a cell or group of cells which have direct or indirect effect on cell behavior via biophysical, biochemical, or other routes” (Barthes et al. 2014: 1). According to this explanation, the factors that matter in the cell environment include other cells surrounding the stem cells, the extracellular matrix, and ‘bioactive agents’ such as hormones, cytokines, and mechanical forces. These scientists also sometimes employ the term ‘niche’, which comes from the field of ecology, in almost the same way as microenvironment, using it to explain how stem cells behave in relation to their surroundings, both in vivo and in vitro. Since stem cell research and regenerative medicine are amalgams of various fields and approaches, such as developmental biology, embryology, genetics, cell therapy, and tissue engineering, the concepts used are not shared among all the fields from which they draw. But for many scientists, the concepts are useful to explain microscale interactions between cells, signals, proteins, and materials.
Exerting control over the cell microenvironment or niche is a fundamental aspect of stem cell science and regenerative medicine. Biologically, physically, and chemically, scientists try to control and effectively manipulate the complex and multi-component cell environment in order to obtain cells and tissues for transplantation. For instance, the tissue engineering scientist Julien Barthes and his colleagues (2014: 3) write:
The microenvironmental control over how these cells can keep their plasticity, that is, how they can stay quiescent and be utilized by the body only in case of necessity under healthy conditions, is a benchmark that needs to be met by engineered tissues. Moreover, failure to control the microenvironment of stem cells can also have deleterious effects such as dedifferentiation and subsequent tumor growth.
If efficient controls and manipulations fail, the cell microenvironment could cause a crisis of overproduction and, in turn, cancer. Hence, the capacity and potentiality of cells depends largely on the microenvironment that humans make in a dish: it is this environment that decides whether cells remain in their stem cell state, differentiate into other types of cells, or become a tumor. This is what makes them highly relational objects. To capture their potentiality, scientists must arrange the cell microenvironment, which is the minimum scale of the ecological trap. But the traps does not remain stable. Within the cell microenvironment, cells interact with their environments and transform themselves. Reversely, cells also influence their environments, and the environments transform accordingly. Cells and their microenvironments are always being made and remade.
Although the Murakami laboratory members may not have commonly used the words ‘microenvironment’ or ‘niche’, what they were doing every day was arranging more suitable environments based on the changing conditions of the cells and the goals of their clinical studies. In addition to preparing an appropriate environment for the cells, attentive care was crucial for these studies because the laboratory needed to culture new iPS cells from each patient who was waiting for a transplantation. By contrast, most scientific laboratories use established cell lines, which are standardized and thus easier to manage. Culturing unique iPS cells from individual patients’ own cells took several months—and because the cells derived from different patients each have different characteristics and needs, this process was extra challenging.
As a result, Murakami hired special technicians who could culture cells properly. Due to their experiences with culturing a variety of iPS cells and other types of cells, they knew how to tinker with the cell microenvironment as needed. In appreciation of their special skills and embodied knowledge, Murakami called these technicians “iPS sommeliers.” As I have discussed elsewhere (Suzuki 2015), through training, their bodies learned to be affected by and to affect cells. They became able to notice subtle differences in and across cells, which was crucial for judging the timing and amount of chemicals to be used in the dish. When noticing these differences, the laboratory members used onomatopoeia—a form of language that is extensive and highly nuanced in Japanese. Thanks to a wide variety of onomatopoeic words, they were able to describe the nuances of many different states of cells. In this way, their sensory systems were “becoming with” the environment of the cells, as Donna Haraway (2008) might put it, which in turn affected the transformation of cells. Looking at these abilities through the lens of traps, iPS sommeliers were like observant spiders who constantly fixed their webs and were able to respond to unexpected events.
At first, proper individualized care is what enabled the sommeliers to make the traps more flexible and attuned to the iPS cells’ specificity. However, for the clinical study and the clinical trial to proceed, simply cultivating healthy cells was not enough. The laboratory needed to guarantee the safety of the cells and the efficiency of transplantation on a large scale. In the next section, I demonstrate how the Murakami laboratory arranged special infrastructures and documenting systems as an extension of the cell microenvironments in the petri dishes.
The Cell Processing Center
In preparation for the clinical study, the laboratory members knew that RPE-iPS would be transplanted soon into a patient's retina. Therefore, the cells needed to be cultured in a clean environment, safe from bacterial contamination. The special facility that was established to culture cells was called the Cell Processing Center (CPC), which consisted of several work rooms. Built and designed specifically for the RPE-iPS clinical study, the CPC's aseptic (germ-free) operating environment allowed for the culture of cells. To get in, one was required to wear white sterile clothing from head to toe, resembling a spacesuit. In order to take care of the cells and their microenvironments properly, it was important to maintain and care for the facility and equipment as well. The surrounding laboratory air was, after all, part of the cells’ indirect environment. As such, a stable temperature, a regular CO2 concentration, and general cleanliness were rigorously maintained within the CPC. Outside, there was a room equipped with huge air conditioning machines. To control the air inside, pipes stretched around and throughout the facility. This machinic infrastructure was necessary, first, because the cells’ environment needed to be stable, and, second, because these infrastructures protected the cells from dust and bacterial contamination.
To maintain the CPC as a proper environment for cells, there were three major kinds of work that needed to be done: maintaining the machines, cleaning the center, and keeping documents. Several of the technical staff on the CPC team were charged with those tasks. One member, Mamoru, was given the special responsibility of checking whether all of the equipment was operating normally. Since the CPC had been running for several years by the time I arrived, the machines had started to deteriorate. When Mamoru went around the CPC to check the machines, he relied on auditory senses rather than vision: he was very careful to listen to noises that were different from normal. Like the iPS sommeliers, Mamoru's work with bodies, machines, and cells was entangled in this ecological trap.
Mamoru's second important task was supervising regular cleaning. To keep the inside of the CPC pristine, staff from a cleaning company came once a week to check every room and count the number of dust and bacteria particles, using portable instruments called ‘particle counters’. Mamoru explained to me the uncertain relationship between cells and the cleanliness of the CPC: “Even if there is a high concentration of dust, it does not automatically mean the cells are spoiled. I mean, there is no direct relationship between the dust and cells. But what I'm doing is keeping a stable environment for cells.” Taking care of this indirect environment was key to trapping cells in order to realize the laboratory's goals within regenerative medicine. Like a spider taking into account the weather, the wind, the temperature, and other ambient factors, Mamoru did his best to set up an environment where his prey could be captured.
Another complementary kind of work that was done to guarantee the safety of cells was making piles of documents that would be submitted to the MHLW as part of the approval process for the clinical trial. The CPC team had been recording everything they could about their experimental procedures: their cleaning methods and culturing processes, the lot numbers of chemicals and culturing media, the status of cells, the results of quality control testing, and so on. That way, if something went awry, they could go back and trace what had gone wrong. However, before they could start recording the actual results of the clinical trial, the team needed to think about what form to use. What kinds of information should be included in the document? Since there were no precedents for clinical trials using iPS cells, their situation was like groping in the dark. When procedures or other factors of the clinical study changed, the members had to revise the form of the documents. In this case, it was as if a spider had found herself building a new kind of web in a totally unfamiliar place, unsure of what kind of prey she might catch.
Emergent Properties: Co-development of iPS Cells and Their Ecological Trap
Although CPC members like Mamoru had become used to managing and working within this very specific environment, there were always changes to how the CPC was run and how iPS cells were cultured. Constant adjustments were necessary. For instance, as the scientific exploration of iPS cells proceeded, new recipes to establish iPS cells were continuously being proposed. After the CPC team had adopted one recipe (inducing five genes and co-culturing them with feeder cells), another recipe that did not use feeder cells was proposed by the Yamanaka laboratory. Since the latter recipe was much easier, the team wanted to switch to this new one. However, as I observed, this shift ended up presenting some hurdles.
Even as new recipes were being developed, the standards and norms for scientifically evaluating these cells were still being decided. This meant that it was difficult to prove that the cells established by different recipes were identical. Therefore, CPC team members and their genetic scientist collaborators were trying to find genetic markers that were specific to iPS cells and RPE. However, despite the geneticists’ best efforts, they were unable to identify exact indicator markers. Such problems are common because the genetic sequences of each person's cells differ, and genetic comparison generally is very uncertain. In addition, in order to change the recipes, the team realized that they would need to change the protocols they had decided on, and this required them to resubmit a huge number of documents to the MHLW. In the end, the members gave up on adopting the easier recipe for the first clinical study, although some regretted that their recipe had been decided at too early a stage in the process.
This episode shows that the decisions made about which experimental protocols to follow are dependent on various factors and contingencies. For instance, in addition to figuring out the best recipe, the team needed to consider new surgery techniques, the design of the facility, the funding budget, the available technicians, as well as the changing regulatory system at the national level. If the regulatory system changed once more, the members knew that they would need to prepare new documents and alter their strategy again. In addition, they had to keep in mind the considerable investment of time it would take to train iPS sommeliers and inculcate them with culturing skills.
In other words, the recipes for iPS cells, surgery and culturing techniques, the training of iPS sommeliers, and regulatory frameworks were all practices in the making. Because of these uncertainties, the team could not deal with the different issues one by one. Rather, they needed to make decisions from a position of uncertainty by considering various factors as they arose. Meanwhile, what iPS cells were and what they could do was being decided by these arrangements. From the perspective of the ecological trap of cells, then, iPS cells and their environment were in a dynamic and reciprocal relationship, such that the potentiality of cells was not only the prey object, but an effect of the arrangement and configuration of the trap itself.
The concept of ‘emergent properties’, as discussed by the biologist Scott Gilbert and the philosopher Sahotra Sarkar (2000), is very helpful for understanding this co-development of the cells and traps. Gilbert and Sarkar propose this theory as a means to explain complexities in developmental biology instead of relying on reductionism, which is the dominant way of thinking in chemistry, physics, and most of biology. They insist that complex entities, including proteins, cells, organisms, and ecosystems, cannot be explained by the properties of their parts. They argue that complex wholes are “inherently greater than the sum of their parts in the sense that the properties of each part are dependent upon the context of the part within the whole in which they operate” (ibid.: 1). Although this concept was proposed to help biologists explain complicated phenomena within bodies, it is also useful for explaining the relations between iPS cells, their environments, and humans.
Through the lens of the ecological trap, as iPS cells emerge, a whole range of practices and processes also come into shape: standardizing methods for raising cells, training technicians, designing laboratory spaces, and so on. These elements are tinkered with little by little, because iPS cells do not respond well to drastic changes in their formulas or routines. Rather, the potentiality of iPS cells is captured through the looseness and flexibility of their living arrangements. Like a spiderweb, the iPS cell trap slowly gets spun, torn, fixed, and remade. Importantly, the uncertain and complicated nature of the cells affects practices not only for team members but also for wider institutional assemblages, namely, Japanese legal and regulatory systems.
Transforming the Regulatory System
As noted earlier, in parallel with Cell Processing Center Cell Processing Center its small-scale clinical studies, the Murakami lab had started to prepare for a company-led clinical trial, which would involve many more patients. Yoko Murakami knew that since the transplantation of cell products derived from artificial cells was a very new treatment, the PDMA and the MHLW would be hesitant to approve her study. More than that, there were no suitable categories to even assess her proposed cell therapy within the existing regulatory systems.
At the time when Murakami started her research, the only two categories used by the PMDA in Japan were ‘drugs’ (pharmaceuticals) and ‘medical devices’. Simply put, a drug is considered a chemical substance whose components are well known, while medical devices can take many different forms, such as contact lenses, ultrasound scanners, or blood glucose monitoring kits. According to global health scholar Bronwyn Parry (2018), the key distinction between drugs and medical devices is their materiality and mode of action: “Medical products or pharmaceuticals are considered to act by pharmacological, metabolic, or immunological means—through diffusion within the body and through medical devices by physical, mechanical, or thermal action upon the body” (ibid.: 105).
However, the character of iPS cells was not applicable to either category, and this caused difficulties for the PMDA. Based on the pre-existing PMDA review process, the efficiency of a drug or technology should be evident. However, the ways that cells work in bodies could not be understood by the existing pharmaceutical evaluation system. In the case of drugs, one or some active ingredients can be chemically identified. Thus, pharmaceutical companies are able to show the correlation between a drug's active ingredients and specific changes in a human body. But cells produce various factors at the same time, and it is therefore difficult to define which factors are effective and which are not. The cell products that Murakami's laboratory created for transplantation were made of cells and various chemicals. Since the cells were always changing according to their surroundings, the components of the cell products were difficult to define. Furthermore, once transplanted into a body, cells act in various ways: they may adhere to other cells, proliferate, differentiate into other kinds of cells, or migrate.
This biological nature of iPS cells presented other problems as well. Since pharmaceuticals and medical devices are mass produced, all of the products in the same lot are considered to be of the same quality. They can be tracked and managed by their ‘production lots’. This particular production unit of assembly is very important for managing the safety of the product. However, in the case of iPS cells, even cells in the same dish can be different or can change when affected by their environment. Thus, cells require a different way of understanding their unit of production lot.
From an early stage, then, Murakami had approached the MHLW and the government to actively advocate for changing the regulatory system. Following Yamanaka's Nobel Prize win, and in response to increasing public expectations around the potential for iPS cells to revolutionize regenerative medicine, Murakami pushed even further. Along with other medical scientists, she lobbied and used mass media effectively to draw attention to their work. Murakami emphasized the global competitiveness of regenerative medicine, arguing that Japan needed to take advantage of this ‘Japan made technology’ not only for the progress of science, but also for Japanese medicalization and industrialization to remain competitive on a global scale. In order to do that, the government needed to change its regulations. “If the Japanese regulatory system could enact proper regulations for iPS cells, Japan could win,” she said pointedly in one of our interviews.
These efforts paid off. In 2013, the Japanese government amended the Act on the Safety of Regenerative Medicine and the Pharmaceutical and Medical Device Act, the two laws that governed clinical trials, and made it quicker to receive approval. At the same time, a new category, called ‘cell products’, was created to promote regenerative medicine. In other words, since the character of iPS cells was so different from that of drugs and medical devices, the government was forced to make an entire new legal category.
Meanwhile, the questions of how to evaluate the effectiveness of cells and how to define particular cells are still being discussed by experts. As the ecological trap emerges and stabilizes, the answers to these questions will gradually be decided. But what this story shows is that compared to the rigid evaluation systems governing medical products and pharmaceuticals, cells require a lot more flexibility, as well as cooperation between various experts, such as culturing technicians, scientists, clinicians, regulatory officers, pharmaceutical companies, regulatory scientists, and government officials.
Conclusion
This article has explored how humans create ecological traps to capture novel iPS cells in order to take advantage of their capacities for curing diseases and treating human bodies. The concept of the ecological trap offers a better understanding of this emergent biotechnology and how it has given form to a particular entanglement of cells, humans, and experimental systems, within specific infrastructural and regulatory settings. The unique materiality of iPS cells, as highly relational objects, makes it impossible for this biotechnology to follow a linear path toward commodification and rigid standardization. On the contrary, trapping iPS cells requires a loose, holistic, and multi-scalar approach.
The ecological traps we have discussed are aimed at emerging properties of stem cells. Since stem cells are mercurial living beings that transform their morphology and nature according to their surroundings, only by arranging and tinkering with heterogeneous elements little by little are humans able to capture their potentiality. This example sheds light on the mediation and co-production of cells and humans, putting emphasis on the processual relationality of these entities over their ontologically predetermined character. To conclude, I want to return to the point that the ecological trap is a place where cells can survive but also a place where cells and humans can co-habitate. Like iPS sommeliers who attune to iPS cells by affecting and being affected, societies must change in order to accommodate cells.
As humans try to capture the potentiality of these cells for their own purposes, they are also obliged to transform wider assemblages. IPS cells have already forced Japanese regulatory and evaluation systems to change to account for biological complexity. Trapping these cells requires less reductionist understandings of life that are sensitive to the emergent properties of cells, bodies, and environments. This means that Japanese society has been forced to transform according to what iPS cells are becoming. The traps that existed before to harness biological life for technological and commercial purposes are dissolving and transforming into more spiderweb-like entanglements. Or, to put it differently, humans are being captured by cells.
As mentioned above, scholars in the STS literature have tended to argue that life itself is becoming more fragmented, as its core elements—cells—are objectified and commercialized. However, the assemblage I have traced here, starting in the cell culturing room at the Murakami laboratory and moving beyond to the realm of Japanese science and government policy, points to a different conclusion: iPS cells resist unilateral flows. As humans try to capture the potentiality of iPS cells, they are forced to transform themselves and the institutional assemblages they work in. The cells have compelled scientists and authorities to rethink pre-existing governing frameworks to accommodate more, not less, complexity in their understandings of life itself. The concept of the ecological trap thus provides one framework that STS scholars might look toward when grappling with the unstable relationships that are emerging due to the development of new biotechnologies.
Acknowledgments
I would like to thank Atsuro Morita, Casper Bruun Jensen, and my editor, Emily Sekine. I also thank the anonymous reviewers for their comments. Finally, I wish to thank all of the scientists and technicians at the laboratory.
Notes
While the original reprogramming factors are Oct4, Sox2, Klf4 and cMyc (Takahashi et al. 2007), each of the factors can be replaced by related gene factors, small molecules, or chemicals.
As Mikami (2014) argues, particularly after Japan's loss in World War II, scientific innovation has become associated with Japanese nationalism. Science is considered an important area for policymaking because it is viewed as a main driver of the Japanese economy.
From 2012 to 2016, I went to the laboratory once or twice a week to interview laboratory members and observe scientific experiments.
I use pseudonyms for the name of the laboratory and all of its members.
Among these various explorations, embryonic stem cells have been discussed, but iPS cells have so far received less attention.
The concept of the ecological trap could be read as a form of ‘assemblage’ (e.g., Ong and Collier 2008) in the broader sense. However, by using the narrower concept of the ecological trap, I aim to emphasize the unstable ontological relationality of cells and human society. Moreover, by emphasizing the ability of iPS cells to elude human capture, my goal is to propose a different perspective on the development of biotechnologies and the commodification of life, which I hope will offer a new path for understanding the workings of biocapital within STS. I thank the anonymous reviewers for leading me to clarify this concept.
The laboratory closed in the same institute a few years ago, and the lab transformed into a venture company.
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