Stem Cell Biotechnology Series: Ethical Considerations and Future Perspectives
Foreword
The field of stem cells is brimming with promise and intrigue. As our understanding of these remarkable foundational components of life continues to evolve, so does our ability to harness their extraordinary potential. Stem cells have captivated the minds of scientists, medical professionals, and the curious alike, presenting unparalleled opportunities to revolutionise healthcare and regenerative medicine. This series of articles aims to unravel the mysteries of stem cell differentiation, explore the mechanisms that govern their self-renewal, and examine the factors that shape their destiny. Within these articles, readers may discover the immense potential of induced pluripotent stem cells (iPSCs) to reshape personalised medicine while uncovering their awe-inspiring regenerative capabilities. Moreover, this series sheds light on the critical challenges and limitations inherently intertwined with this field, from ensuring the safety and efficacy of stem cell therapies through navigating the complex terrain of regulatory frameworks and public perception, to debating ethical uncertainties.
This series is divided into eight articles:
Stem Cell Biotechnology Series: Ethical Considerations and Future Perspectives
Stem cell research epitomises the vanguard of scientific promise and holds the key to breakthroughs in the understanding and treatment of various medical conditions. Nevertheless, this pioneering field is fraught with ethical dilemmas. Foremost among these is the debate over the origin of stem cells and the moral status of the unimplanted human embryo. A profound dichotomy emerges, pitting against each other two aspects that have often been at odds—the potential for scientific progress and the moral considerations about human life. This article will explore the ethical issues surrounding the use of various types of stem cells and the philosophical aspects related to the moral standing of early human life.
The Potential of Stem Cells
The impressive ability of stem cells to differentiate into a wide variety of cell types has sparked enthusiasm within the medical community, researchers, and the general public. The imperative of stem cell research is to unravel the intricate molecular processes that govern cell specialisation, tissue organisation, and organ development. Stem cells play a crucial role in addressing diseases for which there is no cure, making them invaluable for scientific exploration (Volarevic et al., 2011). The scope of stem cell research extends to the treatment of genetic disorders and the generation of novel stem cell-derived human tissues and biomaterials, with significant implications for pharmaceutical genomics and regenerative medicine. Many severe and presently incurable diseases, such as Alzheimer's, Parkinson's, diabetes, paraplegia, and heart attacks, arise from the loss of cells that the body struggles to regenerate naturally. Stem cell-based therapies, particularly cell replacement therapies, aim to address this challenge by replacing or repairing damaged tissues (Wang et al., 2023; Yamazaki et al., 2020). While some stem cell therapies, such as bone marrow, skin, and corneal stem cell transplantation, have gained approval, others, targeting conditions such as diabetes and Parkinson's disease, are still in pre-clinical research. Beyond disease research, stem cells are transforming the drug development process by simulating conditions in the laboratory using reprogrammed iPS cells and stem cell lines. This approach provides helpful insights into the causes and progressions of genetic diseases and offers a more reliable alternative to the traditional reliance on animal testing (Liu et al., 2023). The advent of organoids, miniature organs derived from stem cells, has introduced a revolutionary approach to drug testing. These three-dimensional structures closely mimic natural organ configurations, providing a more accurate understanding and reducing reliance on animal models (Takahashi et al., 2021).
When Does Life Begin?
One of the most heated aspects consistently raised in the moral debate about stem cells is their source. As discussed throughout this series, embryonic stem cells are only present during the very early stages of embryonic development. The resulting entity is called a blastocyst and is scientifically considered to be only a cluster of cells (Zhang et al., 2006). Human embryonic stem cells (hESCs) hold immense promise, displaying the ability to differentiate into cell types representing all three germ layers—endoderm, mesoderm, and ectoderm—both under controlled laboratory conditions and in living organisms (Reubinoff et al., 2000). This potential offers avenues to advance our understanding of early human embryology and to develop cell replacement strategies to treat various diseases. However, the ethical dilemma surrounding the destruction of human embryos has impeded the swift progress of hESC-based clinical therapies. At the heart of the debate on embryonic stem cell research is the contentious issue of the moral status of embryos (Volarevic et al., 2018).
While it is universally acknowledged that embryos possess the potential to develop into human beings, different beliefs shape the moral considerations attributed to them. Some individuals, guided by religion and moral conviction, assert that human life begins at conception, giving the embryo the same moral status as an adult or a live-born child. From this perspective, extracting embryonic stem cells by taking a blastocyst and removing the inner cell mass is seen as equivalent to murder (Block, 2010). Conversely, others believe that the embryo attains personhood at a later developmental stage than fertilisation and advocate for a middle ground. This middle ground recognises the early embryos as deserving of particular respect as potential human beings while permitting their use for research under specific conditions, including scientific justification, careful oversight, and informed donor consent (Kondro, 2001). Opposition to human embryonic stem cell research is often tied to broader stances on abortion and the ‘pro-life’ movement (Lowe & Hayes, 2019).
This debate has led to diverse legislation worldwide, with varying approaches to regulating hESC research. For instance, the United Kingdom permits hESC research but prohibits nuclear transfer (NT) for reproductive or therapeutic purposes, while Italy imposes a complete ban on all hESC-based research (Stojkovic et al., 2005). In the United States, the production of new hESC lines that require embryo destruction is prohibited, and research using existing lines is restricted. Legal constraints and ethical considerations have steered the focus toward animal models rather than direct human studies in hESC research (Volarevic et al., 2018). There are also safety issues that come into play concerning the clinical use of hESCs. Their pluripotency, which allows for the generation of different cell types, makes it difficult to control their behaviour after transplantation. This lack of control means that transplanted undifferentiated hESCs can lead to the development of teratomas—tumours composed of different types of tissues, such as bone, hair, muscle, and teeth (Prokhorova et al., 2009).
Acquiring Cells
The derivation of pluripotent stem cells from fetal tissue after abortion presents a viable avenue for scientific exploration, albeit it is fraught with ethical controversy due to its association with abortion, which many people find objectionable. In the United States, for example, fetal tissue research is permitted by federal regulations, but under one condition: the decision to donate tissue for research must be made after the decision to terminate the pregnancy. This requirement is intended to prevent a woman's decision to terminate her pregnancy from being influenced by the idea of donating tissue for research (Lo & Parham, 2009). This ethical dilemma gains further relevance and complexity when considered alongside the escalating unease surrounding oocyte donation for research purposes, particularly in the aftermath of the Hwang scandal in South Korea. This infamous incident involved the falsification of widely accepted claims regarding the derivation of human somatic cell nuclear transfer lines. Beyond scientific misconduct, the scandal brought to light other troubling issues, including improper compensation for oocyte donors, substantial deficiencies in the informed consent process, undue influence on both staff and junior scientists to participate as donors, and an unacceptably high rate of medical complications stemming from oocyte donation (Chong, 2006).
Sometimes, women who are undergoing fertility treatment choose to share their eggs with researchers, even if it may reduce their chances of getting pregnant because fewer eggs are available for their fertility treatment. In these cases, the doctor overseeing egg retrieval and fertility care must prioritise the patient's needs (e.g., the fertility treatment). The best-quality eggs should be saved for the procedure, as not all of them will result in a successful pregnancy and not all embryos will develop well enough for implantation. Any extra material can be donated to researchers for scientific study (Levens & DeCherney, 2008). Certain precautions should be taken to protect the interests of egg donors. For instance, when deciding whether an embryo is suitable for implantation or whether an egg has failed to fertilise, the scientist making these judgments should not know whether the woman has agreed to donate it for research. Therefore, any potential conflict of interest is avoided. Additionally, the doctors providing fertility treatment should not know whether their patients have decided to donate materials for research (Lomax et al., 2007).
The medical risks associated with oocyte retrieval encompass potential complications such as ovarian hyperstimulation syndrome, bleeding, infection, and anaesthesia-related problems. These risks can be mitigated through careful selection, monitoring the number of developing follicles, and adjusting the dose of human chorionic gonadotropin used to induce ovulation or, if necessary, stopping the cycle (Maldonado Rosas et al., 2022; Tober et al., 2023). Given that severe hyperovulation syndrome may entail hospitalisation or surgery, there is an urgent need to safeguard women contributing oocytes for research from the financial burdens associated with complications arising from hormonal stimulation and retrieval. This factor is even more pressing in countries where there is no universal health insurance - ensuring that these women are shielded from the costs of treatment for complications becomes a matter of righteousness (Lomax et al., 2007).
Oocyte donor compensation policies vary widely among jurisdictions, leading to inconsistencies. Providing reimbursement for out-of-pocket expenses is generally accepted as fair, ensuring contributors are not financially disadvantaged by their participation in research. However, the ethical debate amplifies when considering payments beyond reasonable expenses (Spar, 2007). Arguments for and against such payments are diverse. Some express concern that excessive compensation may encourage women, particularly those with limited employment options, to take unnecessary risks, as seen in the Hwang scandal. To allay fears of such undue influence, it may be necessary to educate participants and ensure that the choice is genuine. Another objection is that paying women to provide oocytes for research may undermine human dignity, as it may devalue biological materials and intimate relationships when treated as commodities for sale (Holland, 2001). This ongoing ethical debate stresses the complexity of compensating individuals who contribute to scientific research involving human reproductive material. On the other hand, some argue that it would be unfair to prohibit payments to donors who provide oocytes for research while allowing substantial compensation for women who undergo similar procedures for infertility treatment. They point out that in other research contexts, both men and women receive payment for participating in invasive procedures (Sutton, 2018). Criticism against banning payment for oocyte donation for research raises concerns that women are being denied the autonomy to make decisions for themselves in a somewhat paternalistic way. A more pragmatic view of the situation is that it would simply be impossible to persuade a sufficient number of potential donors without offering compensation (Lo & Parham, 2009).
A Morally Superior Alternative?
Induced pluripotent stem cells (iPSCs) closely resemble human embryonic stem cells in terms of their genetic makeup, physical characteristics, telomerase activity, and ability to differentiate into various cell types (Meyer, 2008). The groundbreaking work of Takahashi and Yamanaka introduced the concept of directly reprogramming somatic cells into a pluripotent state without the need for embryo destruction. This reprogramming involves the up-regulation of specific factors known as the 'Yamanaka factors', including SOX2, OCT3/4, KLF4, and c-MYC (Takahashi & Yamanaka, 2006). The resulting iPSCs, which are derived without harming embryos, offer a morally superior alternative to hESCs. Early iPSC lines were created by introducing genes encoding transcription factors using retroviral vectors, which raised safety concerns. However, researchers have made strides in addressing these concerns by using adenovirus vectors and non-viral methods such as a plasmid with a peptide-linked reprogramming cassette (Woltjen et al., 2009). iPSCs offer an ethical advantage over hESCs by sidestepping the controversies associated with embryonic stem cell research. The process involves a relatively non-invasive skin biopsy, minimising the risks to the donor compared to oocyte donation. Recognising their ethical soundness, the President's Council on Bioethics has deemed iPSCs ‘ethically unproblematic and acceptable for use in humans’, confirming their potential to advance research without raising particular ethical concerns in their derivation or use (PCBE: White Paper on Alternative Sources of Pluripotent Stem Cells - Full Report, n.d.).
As stated in the hESCs discussion, the development of teratomas following transplantation is a major concern that extends to the use of iPSCs. This poses a challenge for personalised and regenerative medicine, emphasising the need for more effective methods to generate purified populations of autologous iPSC-derived differentiated cells. It is crucial to note that iPSCs exhibit genomic instability despite improved differentiation protocols, setting them apart from human embryonic stem cells (Yoshihara et al., 2017).
In vitro, patient-specific induced pluripotent stem cells offer a valuable platform for testing new drugs under patient-specific conditions. Since iPSCs are derived from somatic cells obtained from individual patients, the risk of immune rejection upon transplantation is eliminated (Ghaedi & Niklason, 2019). Furthermore, advances in reproductive technology allow the generation of gametes, such as sperm and eggs, from human iPSCs. While this breakthrough holds the potential to address infertility, it also raises ethical concerns, particularly regarding the potential exploitation of the embryos created (Mathews et al., 2009).
The downstream use of iPSC derivatives raises ethical considerations, especially when it comes to large-scale genome sequencing. Privacy concerns may arise as genome sequencing reveals insights into disease pathogenesis, potentially violating donor privacy (Lowrance & Collins, 2007). Additionally, the injection of human stem cells into non-human animals for preclinical testing raises ethical dilemmas related to religious beliefs or moral considerations about the mixing of human and animal species (Greely et al., 2007). The potential patenting of cell lines derived from biological materials may also conflict with donor preferences, accentuating the balance between respecting contributor autonomy and obtaining scientific benefits (Lo & Parham, 2009).
Shifting attention to a more legislative topic, issues related to informed consent have been extensively documented, particularly in phase I clinical trials. A prevalent challenge observed in cancer clinical trials is the 'therapeutic misconception', where participants often anticipate personal benefits without realising that the primary focus of phase I trials is on safety rather than efficacy (Campbell et al., 2022; Joffe et al., 2001). Early gene transfer trials have shown that descriptions of direct benefits to participants can be vague and ambiguous, leading to misunderstandings. This trend extends to Phase I stem cell-based clinical trials, where participants overestimate the benefits and underestimate the risks. The compelling scientific rationale and optimistic media coverage may contribute to idealistic expectations (Henderson et al., 2004). One way to address these barriers is to improve informed consent in early stem cell trials and to communicate realistically the risks and potential benefits. Researchers must emphasise the experimental nature of the intervention, the uncertainty inherent in phase I trials, and the fact that most participants will not benefit directly from the study. In addition, those in charge must ensure that participants fully comprehend the clinical trial. The central ethical concern regarding informed consent does not lie in the information presented in consent forms, but in what participants truly understand about the process and the end goal (Lo et al., 2008).
Henderson et al. examined how Principal Investigators (PIs) and their consent forms describe the probability of direct benefits for participants. The study revealed a disparity: although only half of the PIs anticipated direct medical benefits for subjects, this expectation was not consistently conveyed to participants. The language used to describe direct benefits within consent forms and PIs' discussions was predominantly vague, ambiguous, and indeterminate. Moreover, some PIs found the question about direct benefit question difficult to answer (Henderson et al., 2004). Although the study was conducted in 2004, the issues raised are still relevant to research today.
Cloning
Cloning is as fascinating as a concept as it is controversial. In biological terms, cloning is the replication of living organisms or the production of identical copies of cells, tissues, or whole organisms. One method that enables this procedure is somatic cell nuclear transfer (SCNT), which gained notoriety with the creation of Dolly the sheep (“Cloning Human Beings”, 1997). Thanks to it, it is possible to generate stem cell lines that are individualised replicas. The unique advantage of being able to tailor stem cell lines to individuals with specific diseases creates unparalleled opportunities to develop in vitro disease models, unravel the complexities of disease pathophysiology and evaluate potential therapeutic approaches. In addition to these encouraging prospects, the use of personalised autologous stem cell transplantation offers significant potential for the progress of regenerative medicine. However, the application of SCNT to human stem cell lines has encountered scientific hurdles and raised controversies and objections. Among these ethical concerns is the deliberate creation of embryos for research purposes. Critics argue that such practices, regardless of the source or method, violate the respect owed to nascent human life. Even supporters of deriving stem cell lines from frozen embryos that would otherwise be discarded, fail to assuage this objection entirely. A counter-argument states that pluripotent entities derived from SCNT are biologically and ethically distinct from embryos, adding depth to the ongoing ethical discourse (McHugh, 2004).
The potential use of SCNT for human reproduction raises further ethical concerns. Issues relating to errors in the reprogramming of genetic material, the risk of severe congenital disabilities and concerns about the violation of human dignity add to the difficult ethical landscape (Jaenisch, 2004). The concept of a cloned child with only one genetic parent, potentially regarded as the product of a designed manufacturing process rather than a natural gift, raises moral, religious, and cultural doubts (Häyry, 2018).
The scarcity of human oocytes for SCNT research has prompted discussions about the use of non-human oocytes to derive lines with human nuclear DNA, known as 'cytoplasmic hybrid embryos'. This proposal introduces an even more agitated response, including fears of creating chimaeras, concerns about violating the natural order and species boundaries, and apprehension about potential attempts to implant these embryos for reproductive purposes. In response to these ethical challenges, proponents of such research emphasise the empirical and pragmatic nature of biological species definitions. They point to existing animal-animal hybrids, such as mules, and argue that human cells are commonly injected into non-human animals in medical research without widespread moral objection. Moreover, they advocate for stringent oversight to prohibit the reproductive use of these embryos and impose limits on in vitro development (Baylis, 2009).
A Broader View: Hard and Soft Impacts
Stem cell research can benefit from adopting a more comprehensive approach to ethical considerations. This broader perspective involves recognising two types of impacts: 'hard impacts' and 'soft impacts'. Hard impacts encompass direct, tangible outcomes such as physical effects or financial consequences resulting from research, technology, or interventions. This category includes risks, side effects, costs, safety, and therapeutic value that affect individuals and society positively and negatively (Swierstra, 2015). On the other hand, 'soft impacts' are less tangible and involve the psychological and social effects of research and technology that influence experiences, perceptions, behaviours, social structures, and moral values. Unlike hard impacts, soft impacts are indirect effects that are not easily measured or quantified (van der Burg, 2009).
Assen et al. used organoid research as an example to illustrate the difference between hard and soft impacts of stem cell research (Assen et al., 2021). Organoids (in-vitro-generated structures that mimic intact organs) bring positive hard impacts by enabling personalised interventions with enhanced therapeutic value. While this innovation could be cost-effective in terms of quality-adjusted life years, it could lead to an overall increase in healthcare costs—a negative hard impact. This financial concern, while crucial, is often overshadowed (Hatz et al., 2014). Beyond these hard impacts, organoid research in personalised medicine could affect the financial sustainability of solidarity-based healthcare systems and influence societal attitudes. In the case of animal research, a hard impact could be the reduction or replacement of animal studies. However, the soft impact involves a potential shift in the perception of animal studies, guided by concepts such as subsidiarity and proportionality (Jans et al., 2018). As organoid technology progresses toward animal-free alternatives, the ethical acceptability of certain animal studies may be reassessed. Recognising both hard and soft impacts is necessary for a full understanding of the ethical implications of stem cell research, as focusing solely on quantifiable results may lead to neglecting necessary elements for the success and acceptance of these interventions.
Future Perspectives
Looking ahead in stem cell research, regenerative medicine holds great promise. The ability of stem cells to differentiate into varios cell types offers the prospect of repairing or replacing damaged tissues and organs. This ability fuels the belief that it will one day be possible to treat degenerative diseases. Reprogramming cells into iPSCs is also a tremendous antecedent of enthusiasm. The burgeoning field of precision medicine stands to benefit greatly from ongoing stem cell research. iPSCs, derived from a patient's own cells, can be used to model diseases in a laboratory setting, providing a platform for studying disease mechanisms and testing potential treatments. The synergy between stem cells and 3D bioprinting technology opens up the possibility of creating functional tissues and organs, with implications for organ transplantation and tissue engineering. This development could revolutionise organ transplantation by overcoming limitations related to organ shortage and compatibility issues. The integration of gene editing tools, such as CRISPR-Cas9, further enhances the versatility of stem cells. Precise tweaking of the genetic makeup of stem cells enhances their therapeutic properties and allows issues such as immunogenicity to be addressed. Overall, the forward perspectives seem exciting. However, progress must be accompanied by ethics and morality. Upholding responsible research practices, ensuring transparency in scientific endeavours, and actively engaging with the public will be paramount. A global and international collaboration in educating collectivities about the stem cells properties will greatly contribute to the fruitful development of new technologies.
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Visual Sources
Cover Image: The only way is ethics: what are the moral obligations of a graphic designer? (n.d.). [Illustration]. Pinterest. https://www.pinterest.com/pin/276127020883229209/
Figure 1: The distinct stages of development and differentiation potential of human stem cells. (nd.d, 2023). [Illustration]. Genomics Research Center. https://www.genomics.sinica.edu.tw/index.php/en/news/latest-news/718-inducing-podxl-overexpression-breaks-a-new-milestone-in-the-efficiency-of-interspecies-chimerism-in-8-cell-embryos
Figure 2: Schematic diagram describing the characteristics of ESCs. Volarevic, V., Markovic, B. S., Gazdic, M., Volarevic, A., Jovicic, N., Arsenijevic, N., Armstrong, L., Djonov, V., Lako, M., & Stojkovic, M. (2018). [Illustration]. Ethical and safety issues of stem cell-based therapy. In International Journal of Medical Sciences 15(1), 36–45. Ivyspring International Publisher. https://doi.org/10.7150/ijms.21666
Figure 3: A supporter of disgraced cloning scientist Hwang Woo-suk participating in a rally calling for him to continue his research (n.d., 2009). [Photo]. The San Diego Union Tribune. https://www.sandiegouniontribune.com/sdut-med-skorea-stem-cells-042909-2009apr29-story.html
Figure 4: What is oocyte donation? (Angün, 2020). [Illustration]. Dünya IVF Clinic. https://www.dunyaivf.com/en/blog/egg-donation-treatment/
Figure 5: An illustration about egg donation in Spain (Utor et al., 2023). [Illustration]. InviTRA. https://www.invitra.com/en/how-to-become-an-egg-donor
Figure 6: Potential applications of human induced pluripotent stem cells. Volarevic, V., Markovic, B. S., Gazdic, M., Volarevic, A., Jovicic, N., Arsenijevic, N., Armstrong, L., Djonov, V., Lako, M., & Stojkovic, M. (2018). [Illustration]. Ethical and safety issues of stem cell-based therapy. In International Journal of Medical Sciences 15(1), 36–45. Ivyspring International Publisher. https://doi.org/10.7150/ijms.21666
Figure 7: Division of stem cells according to public opinion (n.d., 2022). [Illustration]. Save the Cord Foundation. https://www.savethecordfoundation.org/embryonic-versus-cord-blood-stem-cells.html
Figure 8: An excerpt from an interview with a PI. Henderson, G. E., Davis, A. M., King, N. M. P., Easter, M. M., Zimmer, C. R., Rothschild, B. B., Wilfond, B. S., Nelson, D. K., & Churchill, L. R. (2004). [Text]. Uncertain benefit: Investigators’ views and communications in early phase gene transfer trials. Molecular Therapy, 10(2), 225–231. https://doi.org/10.1016/j.ymthe.2004.05.013
Figure 9: How to tap the power of stem cells (Jha, 2011). [Illustration]. The Guardian. https://www.theguardian.com/science/2011/mar/13/ips-reprogrammed-stem-cells
Figure 10: Potential hard and soft impacts of stem cell research and stem cell-based interventions. Assen, L. S., Jongsma, K. R., Isasi, R., Tryfonidou, M. A., & Bredenoord, A. L. (2021). [Table]. Recognizing the ethical implications of stem cell research: A call for broadening the scope. In Stem Cell Reports 16(7), 1656–1661. https://doi.org/10.1016/j.stemcr.2021.05.021
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