stem cell research debate paper

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• v.16(7); 2021 Jul 13

Recognizing the ethical implications of stem cell research: A call for broadening the scope

Lars s. assen.

1 Julius Center for Health Sciences and Primary Care, Department of Medical Humanities, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands

Karin R. Jongsma

Rosario isasi.

2 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 3310, USA

Marianna A. Tryfonidou

3 Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands

Annelien L. Bredenoord

The ethical implications of stem cell research are often described in terms of risks, side effects, safety, and therapeutic value, which are examples of so-called hard impacts. Hard impacts are typically measurable and quantifiable. To understand the broader spectrum of ethical implications of stem cell research on science and society, it is equally important to recognize soft impacts. Soft impacts are the effects on behavior, experiences, actions, moral values, and social structures; these are often indirect effects of stem cell research. The combined notions of hard and soft impacts offer a broader way of thinking about the social and ethical implications of stem cell research and can help to steer stem cell research into a sociable desirable direction. Soft impacts enable researchers to become more aware of the broad range of significant implications involved in their work and deserve equal attention for understanding such ethical and societal effects of stem cell research.

The ethical implications of stem cell research are often discussed in terms of risks, side effects, and safety, which are examples of hard impacts. In this article, Assen and colleagues argue that to understand the broader spectrum of ethical implications of stem cell research on science and society, it is important to recognize the so-called soft impacts.

Introduction

Stem cell science has expanded in the past two decades. These new research possibilities raise ethical and policy questions. While ethical reflections on embryonic stem cells have strongly focused on the moral status of the embryo, this is not the case with induced pluripotent stem cells (iPSCs) and adult stem cells. Ethical reflections surrounding these types of stem cells focus primarily on risks of stem cell interventions, what kind of harm unproven stem cell interventions could cause, how to seek informed consent of patients, and questions about ownership ( Andrews et al., 2015 ; Hyun, 2010 ; King and Perrin, 2014 ; MacPherson and Kimmelman, 2019 ). However, stem cell research has other important ethical implications that are easily overlooked.

For example, between 2013 and 2014, clinical researchers conducted a first-in-human study with a mix of allogeneic mesenchymal stem cells and autologous chondrons as an intervention for stimulating autologous cartilage repair in the knee, with promising results ( de Windt et al., 2017 ). During the clinical trial, there were drawbacks in the recovery of some participants. They did not adhere to the instructions of the researchers to be careful with burdening their knee too much, which inadvertently negatively influenced their rehabilitation process. Possibly, some of the patients believed that the stem cell intervention was more effective than it really was. The drawback was not a direct effect of the stem cell intervention itself. It was an effect of how the stem cell intervention affected patient’s beliefs about the therapeutic value that resulted in an undesirable and unforeseen effect of this intervention. Such a mistaken belief in which the research participant overestimates the benefits of the intervention is often referred to as therapeutic misestimation ( Habets et al., 2016 ; Horng and Grady, 2003 ). This belief can have several causes; it could, for example, have been a result of the positive portrayal of stem cell research in the media ( Caulfield et al., 2016 ). The researchers of the aforementioned study adhered to ethical guidelines, including approval by the Dutch Central Committee on Research Involving Human Subjects, proper informed consent procedures, and taking preventive measures to minimize or mitigate possible harm ( de Windt et al., 2017 ). Despite good preparations and preventive measures, the drawback in recovery was undesirable and, in hindsight, to some extent avoidable. In subsequent studies, researchers and physical therapists used the described example to stress to patients the importance of being careful with mobilizing their knee after surgery.

This example indicates that the existing narrow view of ethical considerations fails to do justice to all ethical implications related to the use and integration of stem cells in society. This view focuses primarily upon issues, such as the harm of unproven stem cell interventions, and side effects, such as teratoma formation, storage of donated tissue, and discussions about ownership ( Andrews et al., 2015 ; Hyun, 2010 ; King and Perrin, 2014 ; MacPherson and Kimmelman, 2019 ). Stem cell research could benefit from a broader conception of ethical considerations, which could contribute to developing effective strategies to enhance the benefits of stem cells and mitigate undesirable effects. This broader conception of ethical implications can be promoted by distinguishing between the narrow view as “hard impacts,” and a type of ethical considerations that is now often being overlooked, referred to as “soft impacts” ( Swierstra, 2015 ; Swierstra and te Molder, 2012 ; van der Burg, 2009 ). The terms hard and soft do not refer to the severity of the impact, but to what is actually impacted.

Hard impacts are characterized by two aspects ( Swierstra, 2015 ). First, there is a causal physical relationship between the research, intervention, or technology, and the effect it has. For example, how a drug (technology) improves the health (the effect), or how a drug leads to an undesirable side effect. Second, the research or technology outcome is quantifiable and measurable, such as the gravity of an immune response, the type of gene-expression pattern of stem cell lines ( Scudellari, 2016 ), and the costs to clinically translate stem cell research ( Neofytou et al., 2015 ). These outcomes could, for instance, indicate an increase or decrease in harm. In other words, hard impacts are direct (physical) outcomes or financial effects of the research, technology, or intervention. It often includes risks, side effects, costs, safety, and therapeutic value. These impacts can be both positive and negative for individuals and society.

Soft impacts are characterized by how technologies, research, or interventions affect experiences, perceptions, actions, social structures, and/or moral values, and are therefore not easily quantifiable or measurable ( van der Burg, 2009 ). In that respect soft impacts are often about the psychological and social effects of research and technology. Compared with hard impacts, soft impacts are outcomes that are an indirect effect of research or technology. An overview of potential hard and soft impacts can be found in Table 1 .

Potential hard and soft impacts of stem cell research and stem cell-based interventions

This paper argues that the notion of soft impacts could help stem cell researchers to become more aware of the wider array of ethical implications involved in their work. The combined notions of hard and soft impacts offer a broader way of thinking about the ethical implications of stem cell research and can help to steer stem cell research and innovation into a desirable direction. Therefore, these terms will be used in this paper as a heuristic tool to exemplify the different ways of thinking about ethical implications of stem cell research and interventions. Taking both types of impacts into account could have merits for responsible development, use, and policy of stem cell interventions.

Hard and soft impacts: Examples

To illustrate the difference of hard and soft impacts of stem cell research, we draw on organoid research as an example and its impacts on personalized medicine, costs, and animal research. An organoid is defined as an in-vitro -generated stem cell-derived structure, mimicking the architecture and physiology of intact organs. These organoids can, among others, be derived from iPSCs and adult stem cells and it has been proven to be a suitable model for disease-modeling research ( Bredenoord et al., 2017 ; de Souza, 2018 ).

A positive hard impact of this type of technology is that it allows for the creation of new types of personalized interventions, with an increased therapeutic value compared with non-personalized interventions, thereby reducing harm. In terms of quality adjusted life years (QALYs), personalized interventions could be cost-effective ( Hatz et al., 2014 ). However, since personalized medicine may lead to an increase in QALYs compared with conventional alternatives, it is likely that overall costs will also increase ( Tiriveedhi, 2018 ). Therefore, the development of organoids for personalized interventions may also increase the overall costs for healthcare. This financial harm is a possible negative hard impact of the success side of this technology.

By focusing merely on the increasing costs of medical research and innovations, one may overlook the soft impacts and how technological developments are embedded in a broader social context. Within this context, organoid research used in personalized medicine could potentially affect the financial sustainability of solidarity-based healthcare systems. An example of solidarity in healthcare is the collective responsibility for paying the costs in healthcare ( Ter Meulen and Maarse, 2008 ). Here, the insured population contributes with a relatively small amount of money that is reserved for paying the total or a (large) part of society's healthcare costs. When organoid research-based innovations indeed lead to considerably increased healthcare costs, it could affect the surrounding system of solidarity and consequentially our attitudes to others.

The differences between hard and soft impacts are as well highlighted in the example of how organoid technology affects animal research. A possible hard impact of organoid research is reduction and/or replacement of animal studies, two of the 3Rs principles (refinement, reduction, and replacement) that contribute to ethical research ( Bredenoord et al., 2017 ). Animal studies have been considered necessary and acceptable—even if controversial—for conducting safety and efficacy studies. Within this context, a conceivable soft impact of organoid technology is that it could affect how animal studies are perceived . Taking the 3Rs of animal studies in mind as an ethical ground rule, it is possible that the ethical acceptability of certain animal studies will be assessed differently because of the possibility to test efficacy and safety by means of organoids. Two concepts are relevant here: subsidiarity and proportionality ( Jans et al., 2018 ). Subsidiarity implies that an action is acceptable because that action is the least morally problematic way of performing research. In that light, organoid technology is generally considered less morally problematic than research on experimental animals. Also, the proportionality of animal research is relevant to consider. This refers to the question whether animal research for testing the effectiveness and safety of new therapies is still proportional ( Jans et al., 2018 ). In the past, studies in which harm was inflicted on animals were considered proportional for acquiring insights into the safety and efficacy of interventions. Nowadays, with organoid technology, animal testing could in certain cases be perceived as disproportional, since it may not be necessary to inflict harm on animals for acquiring insights in efficacy and safety. Therefore, the existence of organoid technology can affect the permissibility of using certain animal studies. Important to note is that, while the field is evolving toward animal-free substitutes, organoid studies are often also not completely “animal-free.” This is due to the fact that Matrigel, which is commonly used to provide the cells with a 3D environment in which they can thrive, is derived from mice ( Bredenoord et al., 2017 ).

By considering hard impacts of a technology or intervention we find multiple advantages. Quantifying outcomes and the assessment of directs risks help to develop safety measures to prevent harm to the health and well-being of patients and research participants. Furthermore, it helps to create a picture of the financial costs. However, quantifying diseases, cells, side effects, and costs, is only part of the ethical implications of these interventions, as the above-mentioned examples explicate. A narrow focus on hard impacts alone comes with the risk of ignoring aspects that are important for the success and acceptance of these interventions. The effect of technology co-producing our morality, such as solidarity and the perception of animal research, is often referred to as “techno-moral change” ( Swierstra, 2015 ). Insights into this techno-moral change through considering soft impacts could contribute to dealing with the ethical challenges of stem cell research. Being oblivious to the soft impacts of technologies and interventions means that the personal and societal effects are missed.

Implications for stem cell research(ers)

Becoming aware of the soft impacts of stem cell research could help researchers to anticipate ethical implications and to develop new skills. As a result, researchers could benefit from soft impacts to positively impact the quality of research; it provides a way of anticipating and understanding the ethical implications of stem cell technologies.

Funding agencies focus increasingly on the social value of research, thereby making it more relevant for researchers to contemplate social value and impact. Soft impacts can help to analyze the social value of research. Focusing on soft impacts enables to not only look at treatment effects on a disease or saving money, but also how the research could potentially improve societal structures and increase social justice. For example, the social value of stem cell research could be that it promotes social justice or helps to empower a group of patients (e.g., destigmatize or physically benefit and enable more participation in society) and helps the target group to flourish.

To better anticipate the ethical dimensions of stem cell research and stem cell-based interventions, we need scientists who recognize both hard and soft impacts. To this end, training or educating in terms of hard and soft impacts could be a tool for recognizing the ethical implications of stem cell research and a step toward contemplating whether to mitigate, prevent, or stimulate certain soft impacts. This could, for instance, be done by creating or implementing courses in biomedical curricula that involve how early patient involvement could be achieved, how the public could be engaged, and what the ethics of biomedical research involve. To prevent that these courses reinforce the focus on hard impacts, ethical training or education should be broadened by reflecting upon how stem cell research affects experiences, perceptions, actions, social structures, and moral values.

Patients can offer valuable insights into how stem cell research could affect perceptions, expectations, and actions. Engaging with patients could give insights into how their disease creates specific drawbacks and expectations. Doing this in an early stage of the research, could aid researchers in preventing the negative and foster the positive impacts in a timely manner ( Supple et al., 2015 ). Courses should address under which conditions early patient involvement is fruitful, how and when this could be implemented in the study design, and which skills are needed to have meaningful interactions with patients.

Similarly, public engagement and science communication could be addressed in curricula or workshops. Ideally, this should lead to interactions and dialogue where there is room for the concerns of the public ( Reincke et al., 2020 ). Such interactions could provide information about possible social and societal implications of stem cell research. Courses should focus upon how such dialogue could be organized and on skills that foster dialogue and lay translation of research.

Furthermore, education about the ethics of biomedical research can stimulate moral awareness by researchers. Using not only factual information but also vignettes and moral scenarios ( Swierstra, 2015 ) can offer insights in how stem cell research could affect social practices, moral values, or social structures. Other possible enabling methods are organizing interventions within research teams and using games and roleplay. These could be embedded in PhD programs and conference workshops. Altogether, these types of activities may promote the moral imagination ( Coeckelbergh, 2006 ) of researchers and students and thereby help them to learn to think about the soft impacts of their work. By doing so, moral imagination could help to understand and anticipate techno-moral change: the way that technology and morality co-shape each other ( Swierstra, 2015 ). It should be noted that educational research about the desired content and design is necessary.

Moreover, the notion of hard and soft impacts establishes a vocabulary and a broader way of looking at and reflecting on implications of stem cell technology. These insights could serve as a starting point for discussions about responsible and desirable stem cell science and what would be needed to create these circumstances.

Implications for policy and regulation

Regulation clusters a broad range of rules or principles governing and evaluating human behavior, thereby establishing boundaries between what should be considered acceptable or indefensible actions. As regulation is influenced by local historical, socio-cultural, political, and economic factors, assessing the hard and soft impacts in both policy debates and outcomes contributes to the development of robust regulation. By doing so, regulation not only reflects society’s shared moral values, but also truly takes into account the broad range of impacts for individuals, communities, and societies. Thus, focusing solely on hard impacts is too narrow, as other important factors for the responsible development and use of stem cell interventions can be overlooked.

To advance responsible development of stem cell interventions, an important question is whether new rules and legislation for promoting ethically sound research should be implemented or how much leeway organizations and researchers should have to deal with the impacts themselves. Rules and regulation might be helpful for conceptualizing and adherence to responsibilities ( Coeckelbergh, 2006 ). For instance, the ISSCR (International Society for Stem Cell Research) provides guidelines for safety and efficacy studies, and guidelines for the derivation, banking, and distribution of stem cell lines. This already helps to prevent and mitigate certain hard impacts of stem cell research, such as loss of reliable data due to contamination of stem cell lines and privacy issues in biobanking ( International Society for Stem Cell Research (ISSCR), 2016 ). As such, guidelines, rules, and regulations help to allocate accountability for processes or operations to researchers or groups of researchers and establish international standards. However, this approach has its limitations, since guidelines, rules, and regulations tend to focus on moral impacts that are measurable or quantifiable. When soft impacts are framed in guidelines, rules, and regulations, we risk that possible socio-ethical challenges might be overlooked. Therefore, guidelines, rules, and regulations cannot and should not do all the moral work. It is important to articulate and explicate the ethical dimensions in stem cell research, where it could help researchers to make better decisions about how the research could be conducted in a desirable and responsible manner. The latter in turn, could ultimately be translated in improved policies or regulations.

Concluding remarks

So far, academic literature, policy, and researchers have focused primarily on hard impacts of stem cell research. Ethical reflection on stem cell research and technology could be broadened by focusing on soft impacts as well. While the term “soft” may sound misleading as being insignificant, the soft impacts are influential for the use and acceptance of these technologies and require more academic and regulatory attention. Broadening the scope of ethical reflection has implications for education, policy, and regulation. The challenge is to find a balance between how much freedom and education researchers should have to deal with possible ethical implications themselves and where policy and regulation could be of help.

It should be noted that, while hard and soft impacts are meaningful heuristic tools to broaden the scope of ethical implications one could assess, the distinction between hard and soft impacts is primarily an analytical distinction, and not always crystal clear ( Swierstra, 2015 ). For instance, certain soft impacts could become hard impacts over time. Nonetheless, anticipating both hard and soft impacts could steer research and innovation into a desirable direction.

More importantly, having a more comprehensive understanding of the ethical implications of stem cell research could help researchers and others to think about how to anticipate and thereby possibly prevent or mitigate possible future challenges instead of dealing with ethical challenges once they emerge.

Acknowledgments

This project has received funding from the European Union's Horizon 2020 research and innovation program iPSpine under grant agreement no. 825925. M.A.T. receives funding from the Dutch Arthritis Society (LLP22). We thank Roel Custers and Lucienne Vonk for sharing their experiences with us and we would like to thank our colleagues at the UMCU for commenting on early draft versions of the paper. Moreover, we thank the anonymous reviewers for their constructive feedback.

Author contributions

L.S.A., K.R.J., and A.L.B. conducted the initial desk research and prepared the first draft of the manuscript. M.A.T. and R.I. commented on and contributed to several draft versions. L.S.A. prepared the final manuscript for submission. All authors approve of the final version.

Conflicts of interests

M.A.T. is a member of the scientific advisory board of JOR Spine board and a scientific advisor for CentryX.

A.L.B. is a member of IQVIA's Ethics Advisory Panel. A.L.B. and R.I. are members of the Ethics Committee of ISSCR.

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• Open access
• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Wojciech Zakrzewski, Maria Szymonowicz & Zbigniew Rybak

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Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

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The Invisible Patient: Concerns about Donor Exploitation in Stem Cell Research

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As embryonic stem cell research is commercialized, the stem cell debate may shift focus from concerns about embryo destruction to concerns about exploitation of the women who donate eggs and embryos for research. Uncomfortable with the polarization of the embryo debate, this paper proposes a more “contemplative” approach than intellectual debate to concerns about exploitation. After examining pitfalls of rigid intellectual positions on exploitation, the paper investigates the possibility of a broader understanding of donation for research where patients are seen as the intended beneficiaries of the donation. Together with other actors, research is perceived as mediating altruistic gift relationships that extend from donors to patients. The paper explores how this broader perspective on “donation for research” can open up new possibilities of understanding donation and addressing risks of exploitation.

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Introduction

Debates about the ethical permissibility of embryonic stem cell research almost exclusively focus on the moral status of the embryo. However, the research also has another sensitive aspect. Since it relies on a supply of fresh ova and frozen embryos, and since commercial interests increasingly are interwoven with the research, worries about exploitation need to be seriously considered. But are they? In an article entitled, “The lady vanishes,” Donna L. Dickenson [ 1 ] called attention to a missing debate, addressing the role of women in the stem cell technologies:

In most public discussion of the ethical issues in stem cell research, only the status of the embryo seems to count. Yet because ova are crucial to stem cell research, there are also important regulatory issues concerning protection of women from whom ova are taken … In most cases and debates, the women from whom the ova are taken have virtually disappeared from view. [1: 43]

More recently, Søren Holm noticed how “arguments relating to the interests of embryo and gamete donors are curiously absent from the particular stem cell banking policy discourse” [ 2 : 265]. He also issued a warning to the field of embryonic stem cell work:

Although some in the stem cell field see themselves as outside of the sphere of reproduction and reproductive policy, it is not obvious that society sees it that way. A lack of proper attention to the rights and interests of embryo and gamete donors in relation to stem cell derivation may over time undermine policy support for the field. [ 2 : 275]

One could wonder why donor interests and risks of exploitation do not figure prominently in policy discussions on embryonic stem cell research. It may, I surmise, partly be due to a fear that concerns about donor exploitation could trigger an equally polarized debate as the concerns about embryo destruction did. With the debate about whether embryo destruction is murder in fresh memory, some in the stem cell field may fear a second polarized debate, this time about whether women are exploited in the stem cell industries. If Holm is right, however, sweeping such concerns under the rug may in the long run prove counterproductive. And unethical, one could add.

In this paper, I suggest that a second polarized stem cell debate is not improbable; that concerns about exploitation of donors need to be voiced rather than silenced; and finally, that bioethics needs to approach these concerns more cautiously and “contemplatively” than in debates for and against doctrines. A contemplative approach to an issue as serious as exploitation can itself seem provocative, of course, because the openness of such an approach could seem to imply openness to exploitation. However, that is why patience and caution are needed. We are considering sensitive normative notions like murder and exploitation, which can be contested in their application to embryonic stem cell research. We need to be aware of how these concepts provide quite worrying images of research practices, and that this property of the images risks preventing an open discussion about the applicability of the concepts. The discussion in this paper is therefore not based on any specific definition of exploitation and will not propose one, but focuses on this general difficulty in concepts that have both descriptive and evaluative aspects. Later in the paper, an attempt in the literature to define exploitation to fit egg donation for research will be examined from this point of view.

Intellectual Dangers of Thick Ethical Concepts

Bernard Williams [ 3 ] distinguished between thick ethical concepts such as “brave” and “brutal,” which have both descriptive and evaluative aspects, and thin ethical concepts such as “right” and “wrong,” which are purely evaluative and action-guiding. “Murder” and “exploitation” can be understood as thick ethical concepts. They have a descriptive aspect combined with a strong negative evaluative action-guiding aspect.

Although the two aspects cannot be separated, this duality of thick ethical concepts, their descriptive-normative Janus face, makes them useful for ideological purposes. If you oppose X, and can demonstrate that X, in fact , involves murder or exploitation (descriptive aspect), then you immediately seem to have demonstrated that X must be condemned (normative aspect). Thick ethical concepts have been used in conflicts to legitimize actions against people who were described as unreliable, greedy, exploitative and even murderous. Since the words are assumed to describe reality, the applicability of the concepts seems to justify us to both condemn and take action against these people.

In relation to the use of thick ethical concepts for ideological purposes, I want to mention three common intellectual dangers or temptations of such concepts.

Dogmatism: The first is that it can be difficult to raise questions about the applicability of such concepts, since it might seem as if you questioned their evaluative aspect. Let us say that you raise the question if embryo destruction is really murder. In the eyes of those who take this description for reality, you can appear like someone who does not take the negative evaluative aspect of the concept seriously. Just asking the question may seem suspicious. The very openness of the question already seems to speak against it and can evoke reactions such as: “Murder is not something to be open-minded about!”

Righteousness: A second troublesome feature is that thick ethical concepts easily produce a good self-image for any ideological movement. Any ideology is on the right side, regardless of which side it is on, since it strives for what its moral vocabulary unites with the good, and opposes what its vocabulary unites with the bad. Any ideology seems to have right and duty to act against what its thick moral vocabulary picks out as blameworthy features of reality.

Moral anxiety: A third problem is that thick ethical concepts can produce anxiety in the form of gnawing suspicions and fears. Most of us are not familiar with embryonic stem cell research, we do not know for sure what it is. Thick ethical concepts can then act as a substitute for what we do not know. They appear in the form of an inner voice that tells us what stem cell research is . This is not a purely descriptive “ is ,” but a double-edged one, for what the voice in the head says the research is could be a frightening, “It is murder.” Since we are ignorant of much, but not of our anxiety, we cannot shake off the thick ethical concepts that have begun to spin in our heads. They seem validated by the anxiety they produce, which is real, and we worry endlessly, caught in a whirlpool of thick descriptive-normative moral language and fear.

In pointing out these dangers of thick ethical concepts, I am not questioning their important functions in our language. It is difficult to imagine human life without these concepts. I am just pointing out how the dual nature of thick ethical concepts can sometimes lock our perspective on reality and make debates on important issues uncompromising. I think many of us have experienced getting caught up in such “thick” descriptions of reality.

Precisely because concerns about donor exploitation deserve careful attention, we need to be aware of the intellectual dangers of thick ethical concepts. The word “exploitation” easily puts us in a state of emergency and can trigger reactions as if we were facing an imminent threat. And that is our difficulty. The investigation is motivated by a concept that simultaneously threatens to short-circuit the investigation.

A Second stem cell war?

Although Dickenson [ 1 ] makes very important observations on a missing issue in the stem cell debate, she does not seem to particularly emphasize the problems surrounding its sometimes almost war-like nature. On the contrary, the metaphor is used to emphasize the importance of another front line:

What unites the two warring sides in “the stem cell wars” is that women are equally invisible in both: “the lady vanishes.” Yet the most legitimate property in the body is that which women possess in their reproductive tissue and the products of their reproductive labour. [1: 43]

I agree, of course, that concerns about women’s status as donors are at least as important as concerns about the status of the embryo and should be highlighted in the discussion about stem cell research. The question I want to raise in this paper is whether these concerns are best addressed by what could be described as a second stem cell war, where the spirit might sometimes be one of using “whatever weapons are available to us” [1: 53]?

Already the first debate, about the embryo, polarized debaters and exhibited tendencies towards dogmatism, righteousness, and moral anxiety [ 4 ]. My question is therefore whether the discussion of concerns about donor exploitation risks becoming a second stem cell war that reproduces similar problematic tendencies. Consider this way of initiating debate about exploitation in stem cell research, by Heather Widdows:

This article will argue that as practices qua practices, both trafficking for prostitution and egg donation for research are exploitive and thus should not be endorsed by feminists. Moreover, the failure to name such practices as exploitive serves to normalize and extend them, thus leading to the exploitation of more women. [ 5 : 6]

There are cases of “egg donation for research” that are alarmingly similar to trafficking for prostitution, as we shall soon see, and Widdows’ concerns are therefore important. Placing trafficking for prostitution next to egg donation for research, however, as if both were uniform practices that are exploitive “ qua practices,” mirrors a tendency in the embryo debate to place murder next to embryo destruction. When an obviously questionable practice is placed next to a practice that you want to debate, the obviously questionable practice easily becomes a model for what the debated practice inherently is like. Such a model can of course be illuminative, but it can also dominate the arguments that are meant to support the similarity between the compared practices. The difference between the practices must therefore also be noticed, as it is the reason why they are placed next to each other. The obviously questionable practice is needed to expose the not so obviously questionable practice. But the claimed similarity between the practices often remains unclear. The similarity then relies on a steady supply of philosophical arguments, which will be questioned, which will be defended, and the debate continues. Footnote 1

Widdows begins her article by discussing trafficking for prostitution, and then she turns to egg donation for research. Here, a second not entirely obvious comparison seems to be made, in that egg donation for research is exemplified by egg donation for research fraud. The story of how a Korean researcher, Hwang Woo-Suk, obtained large numbers of human eggs by coercing young female team members to “donate” eggs to him, and by illegally buying human eggs for his research, serves in the article as a paradigmatic example of “the practice of egg donation for research.”

These not entirely obvious connections between practices give rise to a question. How can trafficking for prostitution, and research fraud, be used as illuminating comparisons when we discuss the intrinsic nature of “the practice of egg donation for research”? What can make these comparisons seem plausible?

My proposal is that the thick ethical concept of exploitation is influencing the investigation into what egg donation for research is. Since the practice of egg donation for research is argued to be exploitive, it seems close at hand to illuminate what egg donation is by connecting it to trafficking for prostitution, and to illegal and coerced egg “donation” for research fraud. The latter practices seem to show more clearly what egg donation for research is , even if at first it did not seem obvious.

Debaters who argue philosophically what embryo destruction or egg donation are , sometimes emphasize what they see as these practices’ morally problematic aspects by using words like “intrinsically” and “inherently.” Combining essentialist vocabulary with thick ethical concepts can, paradoxically, make it sound as if a debatable case such as egg donation for research, by being “inherently exploitive,” or “exploitive qua practice,” was even more exploitive than the obvious cases. Essentialist words can make such a strong impression on us that we fail to see that it is the other way around. We do not say that the assassination of John F. Kennedy was inherently murder; it was murder. We do not say that slavery is intrinsically exploitive; slavery is exploitive. By emphasizing indisputability, the use of essentialist words often inadvertently reveals that the cases are debatable.

The legitimacy of the comparisons that Widdows makes between different practices depends on whether she can argue convincingly that egg donation for research is exploitive as a practice. Why? Because “exploitation” is the conceptual thread that allegedly runs through the different practices and makes it legitimate to place them next to each other. However, the search for a definition of exploitation that can work in the argument already seems to be guided by the need to describe the compared practices as exploitative. Unsatisfied with the fact that Marx’s notion of exploitation does not seem to work for this purpose, Widdows writes:

It is important to retain the elements of power, coercion, and subordination in any definition of exploitation, so that we rightfully can include cases such as Hwang’s junior female researchers. A definition of exploitation that focuses only on disparity of remuneration misses the example out. Particularly for feminists, this caveat is crucial. [ 5 : 20]

The aim with developing a thick ethical concept of exploitation, then, appears to be to enable us to identify exploitation when we see egg donation for research . A definition of exploitation is required that describes egg donation for research and justifies condemning it. The feature that in the end is deemed crucial seems to be gender subordination of women. Just as women’s choice in prostitution is exercised under systematic limitations, since men’s rights over their bodies are systematically privileged, “the need for women’s eggs in the stem cell technologies was simply taken for granted, as if medical research, too, enjoyed systematically privileged access to women’s bodies” [ 5 : 20]. This is proposed to explain also why exploitation of women in the stem cell technologies never was debated academically. I agree, of course, that such an important concern must be addressed. Here I only examine the possibilities of such a discussion and point out certain dangers of thick ethical concepts.

Does an account of exploitation in terms of gender subordination legitimize the connections drawn between trafficking for prostitution, Hwang’s research fraud, and the practice of egg donation for research? It seems to do so, if we view Hwang’s research fraud as a plausible example of egg donation for research. But his exploitation of female team members is a plausible example of “the practice of egg donation for research” only if we already view egg donation for research as inherently exploitive, or exploitive qua practice.

It seems to me that we are caught in a vicious circle of thick ethical concepts and essentialist vocabulary. Without an overview of what egg donation for research is or can become – it varies across legislations and is still in the making – the thick ethical account of exploitation seems to inform us that egg donation for research is exploitative qua practice and that condemning it is the right thing to do.

Concerns about exploitation of women who donate to stem cell research must be addressed. I hope the above considerations indicate the need for a more “contemplative” approach to these concerns, one that is open to differences between practices and to possibilities of change. Otherwise, we are easily exposed to the dangers of thick ethical concepts, which seem to be able to determine what we do not know for sure but need to discuss openly. I doubt that we can say what the practice of egg donation for research is, in definite singular form. The discussion probably needs to start in that uncertainty.

The Invisible Patient

Let me confess my own ignorance. When I hear of egg and embryo donation for research, I take for granted an IVF context and a strict regulation. I do not immediately think of research fraud. Neither do I think of an unregulated egg market in the US, or about poor women in different parts of the world who undergo hormonal treatment and surgery to offer their eggs at underprice, to get some much needed extra money. In other words, when I hear of egg donation for research, I admit that I tend to overlook some rather clear cases of exploitation, which are at the forefront of the articles just cited, and which, of course, need to be addressed.

Nevertheless, my ignorance of certain practices of donation is not completely out of touch with reality. It is in touch with some practices of donation, which are not as obviously exploitive as those of which I am more ignorant. And even if also regulated IVF practices could be exploitive, may we not be able to modify them to counteract the risks? By not talking about “ the practice of egg donation for research,” and by not construing it conceptually as inherently exploitive, we can become more open to the possibility that some present or future practices could be ethically better examples of egg donation for research than Hwang’s research fraud. But are such practices of donation, more worthy of imitation, possible at all? I now turn to this question.

I repeat, we assume an IVF context and strict regulation and control. The woman undergoes hormonal treatment for the purpose of producing eggs to be artificially fertilized and reinplanted in her body, hopefully resulting in one or more longed-for children. In connection with the IVF treatment, the woman is asked if she is willing to donate surplus eggs, or embryos, to some specified embryonic stem cell study. She is informed also that research results may, at some point, be commercialized.

Even after pregnancy, surplus eggs and embryos can continue to be of immense importance to the woman. Not only because she may need them in the future, but also because they are such intimately significant parts of her body. They can become her children. This presents us with a puzzling problem. Why would anyone be willing to donate such sensitive “reproductive tissue” to researchers who wish to develop new stem cell technologies? Especially if the researchers state that they plan to develop medical products from the tissue and offer these products on a market? It can almost sound as if donors voluntarily agreed to be exploited.

To understand the possibility of a willingness among some women undergoing IVF treatment to donate such sensitive parts of their bodies to a research institution, or to “the stem cell technologies,” I believe we need to bring in a figure that so far has been invisible: the patient.

In the critical accounts of egg donation considered above, there is no mention of the fact that the new “stem cell technologies” are meant to function as treatments for future patients. If patients are mentioned, in passing, as in Waldby and Cooper [ 6 : 5, 16], the potential benefits of regenerative medicine are described as “highly speculative” and as “fantasy,” as if patients were practically irrelevant to the field of stem cell research. Legally, the recipient of the donation is some research institution, of course, with its connections to industry and commercial activities. This conglomerate will potentially derive huge economic and other benefits from women’s donations, making the relationship between donor and recipient appear suspiciously unequal, even exploitive. Why would women want to give away reproductive tissue to support research institutions and entrepreneurs? Is it because, as women, they are expected to sacrifice their wellbeing for the wellbeing of others?

A plausible answer, I think, is that the more humanly intended beneficiary of the donation often is the hitherto invisible patient. Egg and embryo donation for research can make a puzzling impression if we leave the patient outside of our field of view. Of course, the donor may consider medical research important and worth supporting, even if it does not benefit any patient. However, we should not overlook the fact that medical research as a whole is related to the treatment of patients, and that even basic research and negative results are important in this broader context. That is why I want to broaden our field of vision, so that we can see the possibility that the legal recipient of the donation mediates gift relationships that extend further; a possibility which can make the donation look different than we first suspected – less asymmetric and puzzling. Of course, the “gift” is not always free for the patient, but it can at least become available to many patients, and even availability can be considered a gift (“gift” is not used here in opposition to “for a fee”; cf. how works of art can be considered as gifts to humanity even though museums charge and books have price tags). In other healthcare systems, the gift would be free, and that is enough for my purposes, which are about seeing possibilities when our way of thinking prevents us from seeing them.

The Intermediating Function of Research and Industry

One could suspect that I bring in the patient only to speak to common normative expectations that women should sacrifice themselves for the needs of others, and that I thereby support the exploitation of women as analyzed by Widdows in terms of gender subordination. My problem, however, is more about our way of looking at donation for research, our difficulty of understanding it, if we do not view medical research in a wider perspective. Altruistic blood donation is easy to understand from a human point of view because the recipient is a needy fellow being, a patient. But how can we understand altruistic donation to a research institution?

Donation for medical research can seem puzzling in the absence of the patient. That is why I bring in the patient who disappeared in the moral concerns that egg donation for research might be exploitive. So, once again, I am not arguing that women undergoing IVF have a care duty to support stem cell research because it will benefit patients in need, or that a donation would be appropriate to reciprocate the gift of IVF treatment. I am only considering the broader context in which a free will to give seems less puzzling or suspicious. What intermediates such a gift relationship from donor to patient, when the direct recipient of the donation is a research institution?

Perhaps a simile explains how we, often without being aware of it, rely on intermediaries who, in their turn, depend on us. It is common knowledge that our digestive tract contains roughly one kilogram of bacteria, without which many of the nutritive substances in the food we eat could not become available to us and our bodies. When we swallow the food, these bacteria are the first eaters, and we have to wait patiently until they have eaten. Even if we know this to be a fact, we do not consciously think that we swallow food to allow microorganisms in our bellies to eat first. We eat for various reasons, but usually unaware of the intermediating function of bacteria.

I suggest that we can look at research and industry as intermediators of gifts from donors to patients. I hope I do not appear condescending if I propose that researchers and entrepreneurs are the societal bacteria that are needed to make the donation available to the patient’s body. We may dislike the idea that our stomachs are full of bacteria, or we may dislike technocrats and capitalists. Still, we rely on bacteria, technocrats, and capitalists. Considered in this wider perspective, who is exploiting whom?

I am proposing a broader way of looking at donation for research that can make it look less puzzling. The proposal is that when someone freely supports medical research by donating tissue, it may be due to some level of awareness of the intermediating function of medical research. (This does not exclude other possibilities, e.g., in systems where the donation gives the woman better conditions for IVF treatment [ 7 ].) The contribution to research will, in the end, hopefully be a contribution to patients. Few, however, are clearly aware of the fact that virtually every successful medical treatment that research contributed to developing was finalized and made available to patients by the pharmaceutical industry. There are so many layers of interdependency at work, when we consider donation for medical research in a larger context. Even generally disliked layers are needed and play at least partially beneficiary roles within the system as a whole. Research alone cannot intermediate altruistic gift relationships from donors to patients. There has to be an industry too, and a healthcare system, and much else. Moreover, just as the proper functioning of bacteria in our digestive tract needs regulation in the form of a diet that supports the right balance of beneficial bacteria, the system of intermediation from donor to patient needs to be regulated and supervised, so that the interdependent actors function harmoniously together. We do not want a system where quacks are free to sell dangerous and ineffective substances to people who are ill, or where stem cell researchers obtain human eggs in any way they see fit. We are surveying a whole society that allows donors to give to patients, if they want, by donating “for research.”

Egg donation for research turns out to be more difficult to isolate as a separate practice than we first thought. Donation depends on a vast system of interdependencies, comparable to what needs to happen in concert in our bodies when we think that we are simply eating. Our concepts do not reflect all of these dependencies, on which they rely for their daily use. This is true not only of “eating,” but also of “donating for research,” and of most concepts. They are simpler than the interdependent realities and relationships that underpin their ordinary use. Having these easily neglected interdependencies in clear view, it becomes surprisingly difficult to isolate separate actors; to see who actually eats first and who eats last; to see who truly is superior and who is subordinate; to see who in fact is benefitting and who the real benefactor is.

The fact that our concepts are simpler than the interdependencies which their daily communicative use presuppose is not a shortcoming. It creates problems only when we expect that the concepts reflect all the relevant facts and relationships. Egg donation for research is a good example. Linguistically and legally such donation is, of course, “donation for research,” donation to some research institution. This is not denied. If this conceptually highlighted relationship is seen as the whole of the donation, however, donation for research can look puzzling and even suspicious “as a practice.” We fail to see the possibility that donating to a research institution can be like handing over a parcel to the post-office clerk. The immediate recipient, the research institution, although conceptually highlighted, can drop off as relatively uninteresting for the donor. We can see this possibility, although the concept represents the research institution (or “the stem cell industries”) as the only recipient.

Having seen that the concept of “donation for research” does not reflect what can make the donation meaningful for the donor – the patient – moral concerns about risks of exploitation in the stem cell technologies transform accordingly. The donation is no longer seen as a transaction between obviously unequal parties, since it is possible for the donor to merely use the direct recipient to give to someone else. Perhaps without being fully aware of it, the donor uses not only research, but a whole system of mutually dependent actors and institutions, such as industry, healthcare, regulation, and governmental supervision. This system can therefore, unexpectedly, be seen as subordinate to the needs of donors who wish to give to patients. Or, this subordination is at least an aspect of the relationship, like the subordination of bacteria with regard to human eating. We can always see the opposite aspect as well, if we want to, since we are considering interdependencies.

Let us sum up, before we move on. In the accounts of egg donation discussed above, the donating woman seems obviously subordinate to the recipient, the research institution, with its connections to “the stem cell technologies.” In that conceptual framework, where the patient is unseen, risks of exploitation appear almost a priori . Another way of looking at donation, however, is to see research, in conjunction with a whole system of interdependent actors, as intermediating gift relationships from donors to patients. The fact that this intermediation engages a multi-billion dollar conglomerate raises reasonable concerns, of course. If these concerns are discussed openly, and the practice is regulated and works within proper bounds, however, there is a possibility that the intermediating system can be made as irrelevant to donors as bacteria in our stomachs are to diners. This possibility does not rule out risks of exploitation, but the risks no longer appear a priori , as in the narrower conceptual framework mentioned above. My hope is that by broadening our view to include the patient, we will be able to discuss relevant risks of exploitation while dealing with the intellectual dangers of the thick ethical concept of exploitation.

Risks of Exploitation when the Humanly Intended Recipient is the Patient

As I mentioned in the introduction, instead of developing a conceptual analysis of exploitation, as in Zwolinski and Wertheimer [ 8 ], this paper describes general intellectual dangers that the word “exploitation” shares with many other thick ethical concepts, especially when the conceptual framework within which we think does not embrace all the relevant features of the practice that we are discussing. Having seen how concerns about exploitation can sometimes be a product of our conceptual framework, which emphasizes the direct recipient of the donation, I now want to exemplify some concerns that a broader view of donation for medical research may raise. Given the self-reflective nature of what I call a “contemplative” approach, I will only suggest four hypothetical cases, and only as an exercise in seeing possibilities that can emerge when we are no longer dominated by a limited conceptual framework.

One risk of exploitation could be well-intentioned attempts to counteract intellectually projected risks of exploitation by paying women for their “reproductive services” to the stem cell technologies, or by giving them a share of future profits. That could establish a tight relationship with the wrong other party, at least if we look at the matter from the broader perspective proposed here. I do not claim that paying for services inevitably means exploitation, but such frameworks invite concerns. Payment accentuates the donating woman’s relationship to a relatively powerful other party, “the stem cell technologies,” which can make exploitation a constant issue. Moreover, since the patient is hidden in such frameworks, such an attempt to counteract risks of exploitation makes practice of the limited conceptual framework that probably projects the concerns from the beginning. However, if the transaction is with the IVF clinic, some women may view donation rationally to be in their own interest, as in an empirical study by Haimes et al. [7: 1211]: “For the interviewees, exchanging eggs for more treatment and therefore for a greater chance of having a baby is a reasonable thing to do.” There are many possibilities.

Another risk of exploitation has to do with the gender differences that Dickenson and Widdows mention. To support an altruistic will to give, a patient perspective may be emphasized. Given normative expectations on women to devote themselves to the needs of others, such a perspective can be a delicate matter to handle. Caution is required to avoid exaggerating patient needs to such an extent that not donating appears unfeeling. Another related risk is presenting the donation as a gift in return for IVF treatment. If an individual freely donates in gratefulness for IVF treatment, this may be alright in the individual case. Framing egg or embryo donation in terms of reciprocation, however, can make the donation seem expected rather than free. Given the normative expectations mentioned above, both an overemphasized patient perspective and a perspective of reciprocation could coerce donation.

After these two possible concerns about exploitation – economization and “sentimentalization” of donation – I want to mention two concerns that donors themselves might have. The first has to do with the fact there are forms of egg donation worldwide that clearly do seem exploitive. Women who donate eggs or embryos in the course of undergoing IVF treatment may worry that their donation goes to institutions that exploit women in other circumstances, perhaps in other parts of the world. Could their free donation support exploitation of less fortunate women? However, these concerns, if addressed openly, could put pressure on research and industry to take a more global responsibility for what could one day, perhaps, deserve to be called, in definite singular form, “the practice of egg donation for research.”

Another possible concern that donors may have is the following. If women (or couples) donate with the patient in mind, they can worry that research and industry will fail to honor the altruistic spirit in which they gave to research. Some actors in the system that makes the donation available to patients may prioritize interests that interfere with the intermediating role that the donor more or less consciously expected. Stem cell treatments will in many cases not be made available to the most needing patients’ bodies, for example, because companies do not believe it is in their shareholders’ economic interest. Let me repeat here what I said earlier, that even accessibility can be considered a gift, that treatment in some healthcare systems is free, and that an open discussion of concerns can change practices. All I want to do here is help us see possibilities when a dominating conceptual framework prevents us from seeing them.

This brief exercise in seeing possible moral concerns can appear inconclusive for regulatory discussions about egg and embryo donation for stem cell research. My aims here, however, are preparatory. I want to counteract a second polarized stem cell debate and to demonstrate a more self-reflective and “contemplative” approach to concerns about exploitation, where we examine also possible intellectual dangers in our own concepts of donation and exploitation. Achieving these aims meant surveying relationships that are presupposed rather than expressed by the concept of “donation for research.” I would like to support regulatory discussions about donation for research that can navigate the conceptual dangers that so easily polarize debates. I would also like to suggest that such broader discussions could consider protecting gift relationships that extend beyond research, through commercialization, all the way to future patients and to future healthcare opportunities.

Protecting Human gift Relationships

This concluding section indicates human functions that altruistic donation for research can have, and which regulators could view as important to support. In a paper entitled, “Gifts of the Body and the Needs of Strangers,” Thomas H. Murray argues that “impersonal gifts acknowledge an entire realm of moral relationships and moral obligations wider than intimate, family ones, and wider still than legal, contractual ones” [ 9 : 35]. If Murray is right and impersonal gifts acknowledge larger dimensions of life, then regulatory discussions about donation for stem cell research could benefit from not putting all the emphasis on individual rights and interests. Individual rights and interests are very important if the sole intended receiver of the donation is the comparatively powerful direct recipient. If donation for research is made with future patients in mind, however, regulation could aim also towards maintaining some buffering distance between donors and direct recipients. Regulation could strive to ensure that intermediators function so harmoniously together that donors need not worry too much about them, but can confidently donate with the patient in mind. This could be an overall aim of regulation: to support a free will to give to unknown others by protecting gift relationships that extend from donors to future patients.

Murray’s paper focused on blood donation where it is relatively easy to see patients as the recipients of the donation. Egg and embryo donation for stem cell research is more complex, partly because the donation is literally “for research,” and partly because so many conjoined scientific, industrial, governmental, and other intermediating efforts are required to make the donation available to the bodies of future patients. If we do not consider the intermediating function of research and industry, and how the literal features of the concept of “donation for research” can obstruct seeing this function, we could be tempted to conclude that

…the claims of the gift relation are destabilized by the fact that donors to stem cell research give not to a fellow citizen [as in blood donation] but to an increasingly capitalized life science sector, which depends more and more transparently on the generally unremunerated labour of the donor. [ 6 : 13]

To avoid that this conceptually tempting view of “donation for research” becomes true, a possibility emerging from the broader outlook of this paper is that regulation could deliberately aim towards protecting donation for research that has patients in mind. Such regulation could enable the complexity of altruistic donation “for research” to illuminate, rather than obscure, how interdependent we are as donors, researchers, funders, industrialists, regulators, authority representatives, healthcare professionals, and patients. It could help us see what our concepts presuppose rather than express literally. I am not thinking of slogans such as, “Together we create better futures for diabetes patients,” which would overemphasize the patient perspective and could act as a form of coercion, as we saw above. I am thinking of well-regulated practices of donation as opportunities for people to cultivate large-mindedness and to acknowledge unselfishness as a human possibility. This implies that several parts of the regulation need to be considered together: not only those parts that deal specifically with donation for research, but also parts dealing with patentability, with biobanks in academic research and industry, with biomedical products, and much else.

In conclusion, it is noteworthy that “literal” views on egg donation “for research” tend to construe relationships in such a manner that donors appear to be the passive party while the recipients are the active ones. Instead of creating such passive donors vis-à-vis powerful recipients, regulation could support active donors to safely exercise altruistic donation with future patients in mind, through a well-regulated intermediary system. By seeing human gift relationships as streams moving through the intermediary system, transporting biotechnologically modified tissue from human to human, donation for research can “remind us that wealth is merely a means to an end, and that not all valuable things can be purchased”[ 9 : 35]. I am not suggesting, of course, that regulation should define patients rather than research institutions as the legal recipients of the donations. However, regulatory discussions can be sensitive to perspectives that are larger than the regulation itself, and this can leave imprints on the regulation. We are envisioning a whole society that allows donors to give to patients, if they want to, by “donating for research.”

Widdows’ use of the example of trafficking for prostitution is more complex, in that it is a rather obvious case of exploitation that nonetheless has been questioned by feminists who fear to appear paternalistic (another thick ethical concept). Widdows’ view is that these feminists fail to identify exploitation when they see it. What is compared, then, are two cases of (allegedly, equally clearly) failing to condemn exploitation of women.

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Acknowledgements

I wish to thank seminar participants at the Centre for Research Ethics and Bioethics at Uppsala University for helpful comments on drafts of the paper. I would also like to thank the two reviewers, whose comments helped me improve the paper both in terms of content and style.

This study was funded by the Swedish Research Council (grant number 2016–02888).

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Segerdahl, P. The Invisible Patient: Concerns about Donor Exploitation in Stem Cell Research. Health Care Anal 30 , 240–253 (2022). https://doi.org/10.1007/s10728-022-00448-2

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Stem cells: past, present, and future

Affiliations.

• 1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
• 2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
• 3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
• PMID: 30808416
• PMCID: PMC6390367
• DOI: 10.1186/s13287-019-1165-5

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

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Oocyte development and formation of…

Oocyte development and formation of stem cells: the blastocoel, which is formed from…

Changes in the potency of…

Changes in the potency of stem cells in human body development. Potency ranges…

Spontaneous differentiation of hESCs causes…

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There…

Culturing of pluripotent stem cells…

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells…

Retroviral-mediated transduction induces pluripotency in…

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their…

Stem cell experiments on animals.…

Stem cell experiments on animals. These experiments are one of the many procedures…

Localization of stem cells in…

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and…

Use of inner cell mass…

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate…

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Embryonic Stem Cell Research An Ethical Dilemma

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Introduction

In November 1998, two teams of U.S. scientists confirmed successful isolation and growth of stems cells obtained from human fetuses and embryos. Since then, research that utilizes human embryonic cells has been a widely debated, controversial ethical issue. Human embryonic cells possess the ability to become stem cells, which are used in medical research due to two significant features. First, they are unspecialized cells, meaning they can undergo cell division and renew themselves even with long periods of inactivity. Secondly, stem cells are pluripotent, with the propensity to be induced to become specified tissue or any “organ-specific cells with special functions” depending on exposure to experimental or physiologic conditions, as well as undergo cell division and become cell tissue for different organs.

The origin of stem cells themselves encapsulates the controversy: embryonic stem cells, originate from the inner cell mass of a blastocyst, a 5-day pre-implantation embryo. The principal argument for embryonic stem cell research is the potential benefit of using human embryonic cells to examine or treat diseases as opposed to somatic (adult) stem cells. Thus, advocates believe embryonic stem cell research may aid in developing new, more efficient treatments for severe diseases and ease the pain and suffering of numerous people. However, those that are against embryonic stem cell research believe that the possibility of scientific benefits of research do not outweigh the immoral action of tampering with the natural progression of a fetal development and interfering with the human embryo’s right to live. In light of these two opposing views, should embryonic stem cells be used in research? It is not ethically permissible to destroy human embryonic life for medical progress.

Personhood and the Scientific Questionability of Embryonic Stem Cell Research

The ethics behind embryonic stem cell research are controversial because the criteria of ‘personhood’ is “notoriously unclear.” Personhood is defined as the status of being a person, entitled to “moral rights and legal protections” that are higher than living things that are not classified as persons. Thus, this issue touches on existential questions such as: When does life begin? and What is the moral status that an embryo possesses? There is a debate on when exactly life begins in embryonic development and when the individual receives moral status. For example, some may ascribe life starting from the moment of fertilization, others may do so after implantation or the beginning of organ function. However, since the “zygote is genetically identical to the embryo,” which is also genetically identical to the fetus, and, by extension, identical to the baby, inquiring the beginning of personhood can lead to an occurrence of the Sorites paradox, also acknowledged as “the paradox of the heap.”

The paradox of the heap arises from vague predicates in philosophy. If there is a heap of sand and a grain is taken away from that heap one by one, at what point will it no longer be considered a heap – what classifies it as a heap? The definition of life is similarly arbitrary. When, in the development of a human being, is an embryo considered a person with moral standing? The complexity of the ethics of embryonic stem cell research, like the Sorites paradox, demonstrates there is no single, correct way to approach a problem; thus, there may be multiple different solutions that are acceptable. Whereas the definition of personhood cannot be completely resolved on a scientific basis, it serves a central role in the religious, political, and ethical differences within the field of embryonic stem cell research. Some ethicists attempt to determine what or who is a person by “setting boundaries” (Baldwin & Capstick, 2007).

Utilizing a functionalist approach, supporters of embryonic stem cell research argue that to qualify as a person, the individual must possess several indicators of personhood, including capacity, self-awareness, a sense of time, curiosity, and neo-cortical function. Proponents argue that a human embryo lacks these criteria, thereby is not considered a person and thus, does not have life and cannot have a moral status. Supporters of stem cell research believe a fertilized egg is just a part of another person’s body until the cell mass can survive on its own as a viable human. They further support their argument by noting that stem cell research uses embryonic tissue before its implantation into the uterine wall. Researchers invent the term “pre-embryo” to distinguish a pre-implantation state in which the developing cell mass does not have the full respects of an embryo in later stages of embryogenesis to further support embryonic stem cell research. Based on this reductionist view of life and personhood, utilitarian advocates argue that the result of the destruction of human embryos to harvest stem cells does not extinguish a life. Further, scientists state that any harm done is outweighed by the potential alleviation of the suffering enduring by tremendous numbers of people with varying diseases. This type of reasoning, known as Bentham’s Hedonic (moral) calculus, suggests that the potential good of treating or researching new cures for ailments such as Alzheimer’s disease, Parkinson’s disease, certain cancers, etc. outweighs any costs and alleviate the suffering of persons with those aliments. Thus, the end goal of stem cell use justifies sacrificing human embryos to produce stem cells, even though expending life is tantamount to murder. Opponents of embryonic stem cell research would equate the actions done to destroy the embryos as killing. Killing, defined as depriving their victims of life, will therefore reduce their victims to mere means to their own ends. Therefore, this argument touches on the question: if through the actions of embryotic stem cell research is “morally indistinguishable from murder?” (Outka, 2013). The prohibition of murder extends to human fetuses and embryos considering they are potential human beings. And, because both are innocent, a fetus being aborted and an embryo being disaggregated are direct actions with the intention of killing. Violating the prohibition of murder is considered an intolerable end. We should not justify this evil even if it achieves good. Under the deontological approach, “whether a situation is good or bad depends on whether the action that brought it about was right or wrong,” hence the ends do not justify the means. Therefore, under this feeble utilitarian approach, stem cell research proceeds at the expense of human life than at the expense of personhood.

One can reject the asserted utilitarian approach to stem cell research as a reductionist view of life because the argument fails to raise ethical concerns regarding the destruction embryonic life for the possibility of developing treatments to end certain diseases. The utilitarian approach chooses potential benefits of stem cell research over the physical lives of embryos without regard to the rights an embryo possesses. Advocates of embryonic stem cell research claim this will cure diseases but there is a gap in literature that confirms how many diseases these cells can actually cure or treat, what diseases, and how many people will actually benefit. Thus, killing human embryos for the potentiality of benefiting sick people is not ethically not ethically permissible.

Where the argument of personhood is concerned, the development from a fertilized egg (embryo) to a baby is a continuous process. Any effort to determine when personhood begins is arbitrary. If a newborn baby is a human, then surely a fetus just before birth is a human; and, if we extend a few moments before that point, we would still have a human, and so on all the way back to the embryo and finally to the zygote. Although an embryo does not possess the physiognomies of a person, it will nonetheless become a person and must be granted the respect and dignity of a person. Thus, embryotic stem cell research violates the Principle of “Full Human Potential,” which states: “Every human being […] deserves to be valued according to the full level of human development, not according to the level of development currently achieved.” As technology advances, viability outside the womb inches ever closer to the point of inception, making the efforts to identify where life begins after fertilization ineffectual. To complicate matters, as each technological innovation arrives, stem-cell scientists will have to re-define the start of life as many times as there are new technological developments, an exhausting and never-ending process that would ultimately lead us back to moment of fertilization. Because an embryo possesses all the necessary genetic information to develop into a human being, we must categorically state that life begins at the moment of conception. There is a gap in literature that deters the formation of a clear, non-arbitrary indication of personhood between conception and adulthood. Considering the lack of a general consensus of when personhood begins, an embryo should be referred to as a person and as morally equivalent to a fully developed human being.

Having concluded that a human embryo has the moral equivalent of a fully-fledged human being, this field of research clearly violates the amiable rights of personhood, and in doing so discriminates against pre-born persons. Dr. Eckman asserts that “every human being has a right to be protected from discrimination.” Thus, every human, and by extension every embryo, has the right to life and should not be discriminated against their for “developmental immaturity.” Therefore, the field of embryonic stem cell research infringes upon the rights and moral status of human embryos.

Principle of Beneficence in Embryonic Stem Cell Research

The destruction of human embryos for research is not ethically permissible because the practice violates the principle of beneficence depicted in the Belmont Report, which outlines the basic ethical principles and guidelines owed to human subjects involved in research. Stem cell researchers demonstrate a lack of respect for the autonomy and welfare of the human embryos sacrificed in stem cell research.

While supporters of embryonic stem cell research under the utilitarian approach argue the potential benefits of the research, the utilitarian argument however violates the autonomy of the embryo and its human rights, as well as the autonomy of the embryo donors and those that are Pro-Life. Though utilitarian supporters argue on the basis of rights, they exclusively refer to the rights of sick individuals. However, they categorically ignore the rights of embryos that they destroy to obtain potential disease curing stem cells. Since an embryo is regarded as a human being with morally obligated rights, the Principle of Beneficence is violated, and the autonomy and welfare of the embryo is not respected due to the destruction of an embryo in stem cell research. Killing embryos to obtain stem cells for research fails to treat embryos as ends in an of themselves. Yet, every human ought to be regarded as autonomous with rights that are equal to every other human being. Thus, the welfare of the embryo is sacrificed due to lack of consent from the subject.

The Principle of Beneficence is violated when protecting the reproductive interests of women in infertility treatment, who are dependent on the donations of embryos to end their infertility. Due to embryonic stem cell research, these patients’ “prospects of reproductive success may be compromised” because there are fewer embryos accessible for reproductive purposes. The number of embryos necessary to become fully developed and undergo embryonic stem cell research will immensely surpass the number of available frozen embryos in fertility clinic, which also contributes to the lack of embryos available for women struggling with infertility. Therefore, the basis of this research violates women’s reproductive autonomy, thus violating the Principle of Beneficence.

It is also significant to consider the autonomy and welfare of the persons involved. The autonomous choice to donate embryos to research necessitates a fully informed, voluntary sanction of the patient(s), which poses difficulty due to the complexity of the human embryonic stem cell research. To use embryos in research, there must be a consensus of agreement from the mother and father whose egg and sperm produced the embryo. Thus, there has to be a clear indication between the partners who has the authority or custody of the embryos, as well as any “third party donors” of gametes that could have been used to produce the embryo because these parties’ intentions for those gametes may solely have been for reproductive measures only. Because the researchers holding “dispositional authority” over the embryos may exchange cell lines and its derivatives (i.e., genetic material and information) with other researchers, they may misalign interests with the persons whose gametes are encompassed within the embryo. This mismatch of intent raises complications in confidentiality and autonomy.

Lastly, more ethical complications arise in the research of embryonic stem cells because of the existence viable alternatives that to not destroy human embryos. Embryonic stem cells themselves pose as a higher health risk than adult stem cells. Embryonic stem cells have a higher risk of causing tumor development in the patient’s body once the cells are implanted due to their abilities to proliferate and differentiate. Embryonic stem cells also have a high risk of immunorejection, where a patient’s immune system rejects the stem cells. Since the embryonic stem cells are derived from embryos that underwent in vitro fertilization, when implanted in the body, the stem cell’s marker molecules will not be recognized by the patient’s body, resulting in the destruction of the stem cells as a defensive response to protect the body (Cahill, 2002). With knowledge of embryonic stem cells having higher complications than the viable adult stem cells continued use of embryonic stem cells violates the Principle of Beneficence not only for the embryos but for the health and safety of the patients treated with stem cells. Several adult stem cell lines (“undifferentiated cells found throughout the body”) exist and are widely used cell research. The use of adult stem cells represents research that does not treat human beings as means to themselves, thus, complying with the Principle of Beneficence. This preferable alternative considers the moral obligation to discover treatments, and cures for life threating diseases while avoiding embryo destruction.

It is not ethically permissible to destroy human embryonic life for medical progress due to the violations of personhood and human research tenets outlined in the Belmont Report. It is significant to understand the ethical implications of this research in order to respect the autonomy, welfare, beneficence, and basic humanity afforded to all parties involved. Although embryonic stem cell research can potentially provide new medical advancements to those in need, the harms outweigh the potential, yet ill-defined benefits. There are adult stem cell alternatives with equivalent viability that avoid sacrificing embryos. As society further progresses, humans must be cautious of compromising moral principles that human beings are naturally entitled to for scientific advancements. There are ethical boundaries that are crossed when natural processes of life are altered or manipulated. Though there are potential benefits to stem cell research, these actions are morally and ethically questionable. Thus, it is significant to uphold ethical standards when practicing research to protect the value of human life.

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Article Details

The Stem Cell Debate: Is it Over?

Stem cell therapies are not new. Doctors have been performing bone marrow stem cell transplants for decades. But when scientists learned how to remove stem cells from human embryos in 1998, both excitement and controversy ensued.

The excitement was due to the huge potential these cells have in curing human disease. The controversy centered on the moral implications of destroying human embryos. Political leaders began to debate over how to regulate and fund research involving human embryonic stem (hES) cells.

Newer breakthroughs may bring this debate to an end. In 2006 scientists learned how to stimulate a patient's own cells to behave like embryonic stem cells. These cells are reducing the need for human embryos in research and opening up exciting new possibilities for stem cell therapies.

Both human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells are pluripotent: they can become any type of cell in the body. While hES cells are isolated from an embryo, iPS cells can be made from adult cells.

The Ethical Questions

Until recently, the only way to get pluripotent stem cells for research was to remove the inner cell mass of an embryo and put it in a dish. The thought of destroying a human embryo can be unsettling, even if it is only five days old.

Stem cell research thus raised difficult questions:

• Does life begin at fertilization, in the womb, or at birth?
• Is a human embryo equivalent to a human child?
• Does a human embryo have any rights?
• Might the destruction of a single embryo be justified if it provides a cure for a countless number of patients?
• Since ES cells can grow indefinitely in a dish and can, in theory, still grow into a human being, is the embryo really destroyed?

Problem Solved?

With alternatives to hES cells now available, the debate over stem cell research is becoming increasingly irrelevant. But ethical questions regarding hES cells may not entirely go away.

For now, some human embryos will still be needed for research. iPS cells are not exactly the same as hES cells, and hES cells still provide important controls: they are a gold standard against which the "stemness" of other cells is measured.

Some experts believe it's wise to continue the study of all stem cell types, since we're not sure yet which one will be the most useful for cell replacement therapies.

An additional ethical consideration is that iPS cells have the potential to develop into a human embryo, in effect producing a clone of the donor. Many nations are already prepared for this, having legislation in place that bans human cloning.

Stem Cell Research Legislation

Regulations and policies change frequently to keep up with the pace of research, as well as to reflect the views of different political parties. Here President Obama signs an executive order on stem cells, reversing some limits on federal research funding. (White House photo by Chuck Kennedy)

Governments around the globe have passed legislation to regulate stem cell research. In the United States, laws prohibit the creation of embryos for research purposes. Scientists instead receive "leftover" embryos from fertility clinics with consent from donors. Most people agree that these guidelines are appropriate.

Disagreements surface, however, when political parties debate about how to fund stem cell research. The federal government allocates billions of dollars each year to biomedical research. But should taxpayer dollars be used to fund embryo and stem cell research when some believe it to be unethical? Legislators have had the unique challenge of encouraging advances in science and medicine while preserving a respect for life.

U.S. President Bush, for example, limited federal funding to a study of 70 or so hES cell lines back in 2001. While this did slow the destruction of human embryos, many believe the restrictions set back the progress of stem cell research.

President Obama overturned Bush's stem cell policy in 2009 to expand the number of stem cell lines available to researchers. Policy-makers are now grappling with a new question: Should the laws that govern other types of pluripotent stem cells differ from those for hES cells? If so, what new legislation is needed?

• DOI: 10.1016/S1049-3867(00)00035-9
• Corpus ID: 12275829

Ethics and politics of embryo and stem cell research: reinscribing the abortion debate.

• Lisa H. Harris
• Published in Women's health issues 1 May 2000
• Political Science, Philosophy, Medicine

11 Citations

Ethical and legal controversies in cloning for biomedical research--a south african perspective., stemming the tide of normalisation: an expanded feminist analysis of the ethics and social impact of embryonic stem cell research, the erasure of egg providers in stem cell science, federal funding for embryonic stem cell research: is the nih's legal line between es cell derivation and research ethically tenable, the ethics of embryonic stem cells--now and forever, cells without end., stem cell debate, performance measures for contraceptive care: a new tool to enhance access to contraception., engineering flesh : towards professional responsibility for 'lived bodies' in tissue engineering, translational research—the need of a new bioethics approach, the feminist transformation of bioethics: an analysis of theoretical perspectives and practical applications in feminist bioethics, 11 references, embryo research: the challenge for public policy., human embryo research, human embryo research: ethics and recent progress., the politics of human-embryo research--avoiding ethical gridlock., ethicists back stem cell research, white house treads cautiously, embryonic stem cell lines derived from human blastocysts., congress may block stem-cell research, derivation of pluripotent stem cells from cultured human primordial germ cells., nih plans ethics review of proposals, in a different voice: psychological theory and women''s, related papers.

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Stem cells: what they are and what they do.

Stem cells offer promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and other cells.

Stem cells are a special type of cells that have two important properties. They are able to make more cells like themselves. That is, they self-renew. And they can become other cells that do different things in a process known as differentiation. Stem cells are found in almost all tissues of the body. And they are needed for the maintenance of tissue as well as for repair after injury.

Depending on where the stem cells are, they can develop into different tissues. For example, hematopoietic stem cells reside in the bone marrow and can produce all the cells that function in the blood. Stem cells also can become brain cells, heart muscle cells, bone cells or other cell types.

There are various types of stem cells. Embryonic stem cells are the most versatile since they can develop into all the cells of the developing fetus. The majority of stem cells in the body have fewer abilities to give rise to cells and may only help maintain and repair the tissues and organs in which they reside.

No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers are studying stem cells to see if they can help to:

• Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with leukemia, Hodgkin disease, non-Hodgkin lymphoma and some solid tumor cancers. Stem cell therapies also might benefit people who have aplastic anemia, immunodeficiencies and inherited conditions of metabolism.

Stem cells are being studied to treat type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before giving drugs in development to people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing may help assess drugs in development for toxicity to the heart.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

• Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Adult cells altered to have properties of embryonic stem cells. Scientists have transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can make the cells act similarly to embryonic stem cells. These cells are called induced pluripotent stem cells (iPSCs).

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells can change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there controversy about using embryonic stem cells?

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Progress in cell reprogramming and the formation of iPSCs has greatly enhanced research in this field. However, reprogramming is an inefficient process. When possible, iPSCs are used instead of embryonic stem cells since this avoids the ethical issues about use of embryonic stem cells that may be morally objectionable for some people.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines, and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't become specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine), and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants, for many decades. In hematopoietic stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases. Leukemia, lymphoma, neuroblastoma and multiple myeloma often are treated this way. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including some degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells also can grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and development of embryonic stem cells.

Embryonic stem cells also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a way to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus also is removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor. And it may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

Researchers continue to study the potential of therapeutic cloning in people.

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• 31 May 2024

What is science? Tech heavyweights brawl over definition

• Fred Schwaller

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If you do research and don’t publish it, is it science? That’s the question at the heart of an ongoing debate on X between entrepreneur Elon Musk and pioneering computer scientist Yann LeCun. Over the past few days, the conversation sprawled into a brawl about the definition of science, attracting thousands of commentators including researchers of all stripes.

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doi: https://doi.org/10.1038/d41586-024-01626-z

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