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Navigating Bioethical Waters: The ethical landscape behind stem cell research

Updated: Sep 26

Author: Kai Sun Yiu


Abstract

The summer of 1996 sparked the beginnings of limitless, scientific potential. Dolly the sheep was born from her surrogate mother, after being cloned by Sir Ian Wilmut and his team from a six-year-old Finn Dorset sheep [1]. Dolly was formed through genetic material, extracted from a Finn Dorset Sheep, being placed into an enucleated egg cell [2]. An embryo was formed following a series of meiotic divisions, and 148 days (about 5 months) after being implanted into the surrogate mother’s uterus, Dolly was born [3]. However, Dolly wasn’t the first mammal to be cloned, with that title being held by two other sheep, Megan and Morag, who had been cloned a year earlier from embryonic and fetal cells [2]. However, this didn’t undermine her significance, through being the first mammal cloned from an adult cell, rather than an embryonic cell. Dolly’s existence disproved past assumptions that specialized cells could only do a certain job, with Dolly being born from a specialized mammary cell which somehow held the genetic information to create an entirely new sheep [4]. This sparked new potential for medicine and biology through the development and research of personalized stem cells, which will be explored within this article through the differences between embryonic stem cells and adult stem cells. 


Introduction

Human cloning can be defined as the creation of a ‘genetically identical copy of a previously existing human,’ or the reproduction of cloned cells / tissue from that individual [5]. Through human cloning, we can gain stem cells from the cloned blastocyst and treat these cells to differentiate into any cells we need for medical purposes. However, this understandably has ethical complications which have made it difficult for scientists to carry out lots of stem cell research. 

This article focuses on the more complex ethical standpoints around stem cell research through some forms of therapeutic cloning, using SCNT (Somatic cell nuclear transfer) and iPSCs (Induced pluripotent stem cells). While SCNT uses embryonic stem cells, iPSCs utilizes the adult stem cells we possess in our bodies to repair damaged cells and tissues. However, both types of cells contain major ethical complications through their uses, allowing this article to tackle the conflict between stem cells' infinite possibilities against their downsides and ethical considerations. 



An insight into modern stem cell research - SCNT and iPSCs

Somatic cell nuclear transfer (SCNT) refers to the process used by both reproductive and therapeutic cloning to produce a cloned embryo. SCNT was first used by Sir Ian Wilmut and his team when cloning Dolly, the sheep:

  1. The nucleus which contains the organism’s genetic material (DNA) of a somatic cell is removed

  2. The nucleus from the somatic cell is then inserted into the cytoplasm of an enucleated egg cell

  3. The egg which contains the nucleus stimulated with electric shocks to encourage mitotic division

  4. After many mitotic divisions, the cell forms a blastocyst, which divides further until it eventually forms an embryo [6]





SCNT is utilized by scientists and researchers worldwide in an attempt to obtain stem cells from the cloned embryo, and use it through regenerative medical practices [6]. A common use of stem cells in regenerative medicine would include the treatment of Parkinson’s disease, where stem cells can restore the production of dopamine in the brain. The in-depth process includes gaining undifferentiated stem cells from the embryo and treating them to differentiate intro dopamine producing nerve cells to treat Parkinsons [7]. 


With the use of SCNT, autologous cells can be formed. Autologous cells are formed from the stem cells of the same individual, meaning the therapeutic material is cloned from the patient, allowing there to be no need for immunosuppressive treatments when differentiated cells are injected into the body [7]. This is due to the autologous cells not being foreign cells, therefore resulting in no probability of the immune system rejecting and damaging the newly introduced stem cells into their body. With stem cell’s ability to ‘treat many human afflictions, including ageing, cancer, diabetes, blindness and neurodegeneration,’ why is there such a lack of breakthrough research on stem cell therapy [8]?


Induced pluripotent stem cells (iPSCs) refer to cells that have been derived and reprogrammed from adult somatic cells (normally taken from a patient bone marrow) [9]. These cells have been altered through the introduction of genes and other factors into the cells to make them pluripotent; this arguably makes them like embryonic stem cells, so they similarly carry the same ethical problems [9]. 


iPSCs are not only seen as unethical, but also take 3-4 weeks of careful lab work to form [10]. The process is extremely slow and inefficient and has a success rate lower than 0.1% [10]. Nonetheless, there are limitless applications for iPSCs such as regenerative medicine, disease modeling and gene therapy. 


Similarly to SCNT, the main advantage of iPSCs is the ability to eliminate any possibility of immune system rejection. The iPS cells are directly generated from the somatic cell of the person’s own body, so there can’t be an immune response to them, as the cells are genetically tailored precisely for the patient they are taken from [12]. The main problem of iPSC is the risk of mutation during the reprogramming of the somatic cells, which can lead to the formation of a cancerous tumor [11]. However, we still need to explore the ethical standpoints in the formation of pluripotent stem cells for research and regenerative science. 


The ethics - SCNT

Through the process of SCNT, we can gain embryonic stem cells from a three-day old embryo. The extraction of the stem cells destroys the blastocyst, a 3-5 day old embryo which can be observed as a cluster of around 180 cells growing within a petri dish, before it fully forms into a fetus [13]. The blastocyst is used as it is at such an early stage of the formation of the fetus, so the cells have not yet differentiated so is arguably ‘not alive’ [13]. 


The ethical argument against the extraction of stem cells is the fact that the destruction of an embryo is arguably killing a fully developed human being. We can look at the position of Senator Sam Brownback, who saw ‘a human embryo...as a human being just like you and me. [13]’ The ethical standpoint around the destruction of embryos is so varied, with George Bush using his veto when US Congress passed a controversial bill, which permitted more funding towards research that used embryonic stem cells [14]. All these ethical considerations surrounding the formation of stem cells are difficult to forget, yet we still need to remember the immense medical and research potential they carry. 


Embryonic Stem Cell Research around the Globe - SCNT 




Map Explanation [15]

  • Dark Brown = ‘permissive’ - Allows various embryonic stem cell research techniques such as SNCT.

  • Light Brown = ‘flexible’ - Lots of restrictions, with embryos only being used under extreme conditions. SCNT is completely banned with human reproductive cloning not allowed. 

  • Yellow = no policy or restricted policy - Outright prohibition of embryonic stem cell research

  • Black Dots - Leading genome sequencing research centers in the world 

The map above illustrates the flexibility around the globe when it comes to the use of embryos during stem cell research. Even in the very few countries which have leading facilities and institutions, there are massive restrictions on the usage of embryos. Even looking at Britain, who managed to vote on the easing of restrictions on the use of embryonic stem cells in 2001, we still have only 7 laboratories across the country [16], [17]. 


The various ethical considerations around the destruction of an embryo makes stem cell research difficult to legalize and even fund. However, the use of stem cells can be arguably seen as the most promising research done for regenerative medicine in the last century. Imagine the ability to cure diseases through replacing cells damaged by infection or being able to grow organs from stem cells to transplant into the thousands of patients waiting for an organ donor. 


What if there was a way to form somatic stem cells without the destruction of an embryo?


The ethics - iPSCs 

Pluripotent stem cells have the ability to form all three of the basic layers in our body (ectoderm/endoderm/mesoderm), which allows them to potentially produce any cell or tissue needed [18]. There are four types of pluripotent human stem cells [19]:

  • Embryonic stem cells

  • Nuclear Transplant stem cells

  • Parthenote stem cells

  • Induced stem cells

All pluripotent human stem cells, apart from Induced stem cells, require human eggs to create. This means that the use of pluripotent human stem cells is limited by ethical considerations; however, induced pluripotent stem cells are different in the way they don’t require the destruction and harm of an embryo. 


These iPSC were discovered over ten years ago by Shinya Yamanaka. The Nobel Prize winner managed to revolutionize biological research by developing a technique to convert adult mature cells into stem cells using the four key genes OCT3/4, SOX2, KLF4, MYC, which are now known as the ‘Yamanaka factors [20].’ iPSCs as a research area has been greatly explored by thousands of researchers around the world, due to the production of the cells being non-controversial in their ability to be derived straight from adult cells rather than embryonic cells. There have been numerous applications of iPSCs in therapeutic medicine. In 2014, RIKEN (The largest scientific research institution in Japan), treated the first patient with iPSC derived retinal sheets, which were able to help with visual function [21]. 2 years later, Cynata Therapeutics (A biotech company), produced iPSC derived product for the treatment of GvHD (Graft versus host disease) [21]. GvHD is a life-threatening disease which can occur when there are complications during stem cell and bone marrow transplants [21]. When the grafted cells are transplanted into the patient, they begin to produce antibodies which interact with the host antigens. This triggers an immune response which may result in an inflammatory cascade, which can cause irreversible organ dysfunction and even death [22]. 


The unlimited medical possibilities iPSCs unlock, paired with the lack of ethical problems they face, makes IPSCs the perfect way to bring stem cell therapy to the masses. 

However, it is not so simple, with the main issue of iPSCs is the need for retrovirus to form these stem cells [23]. The retroviruses used in forming the iPSCs can insert their DNA anywhere in the human genome and trigger cancerous gene expression when transplanted into the patient [23]. Furthermore, the success rate of reprogramming somatic cells into iPSCs is around 0.1%. Not only this, but iPSCs have a strange tendency to not always differentiate, making them much less reliable and successful than embryonic stem cells [23]. 

Nonetheless, research into iPSCs has developed rapidly over the past few years, with scientists and researchers slowly making stem cell therapy using iPSCs available to the public. 


The Pros and Cons of Embryonic Stem Cells and Induced Pluripotent Stem Cells 


Embryonic Stem Cells


Induced Pluripotent Stem Cells  


Pros

  • Can maintain and grow for 1 year or more in culture

  • Established protocols for maintenance in culture

  • ESCs are pluripotent cells that can generate most cell types

  • By studying ESCs, more can be learned about the process of development

  • Abundant somatic cells of donor can be used

  • Issues of histocompatibility with donor/recipient transplants can be avoided

  • Very useful for drug development and developmental studies

  • Information learned from the “reprogramming” process may be transferable for in vivo therapies to reprogram damaged or diseased cells/tissues 

Cons

  • Process to generate ESC lines is inefficient

  • Unsure whether they would be rejected if used in transplants.

  • Therapies using ESC avenues are largely new and much more research and testing is needed

  • If used directly from the ESC undifferentiated culture prep for tissue transplants, they can cause tumors (teratomas) or cancer development 

  • Methods for ensuring reproducibility and maintenance, as differentiated tissues are not certain.

  • Viruses are currently used to introduce embryonic genes and has been shown to cause cancers in mouse studies 


Ethical Concerns

  • To acquire the inner cell, mass the embryo is destroyed

  • Risk to female donors being consented

  • iPS cells have the potential to become embryos if exposed to the right conditions

A comparative table between Embryonic Stem cells and Induced Pluripotent Stem Cells [26]


Stem Cell Therapy Today 

Although no one has been cured of Parkinson's disease (PD) yet, the research from institutions around the world have shown significant development in recent years with ‘experimental treatment.’ On the 13th of February 2023, embryonic stem cells (most likely obtained through SCNT) derived healthy, dopamine producing nerve cells, which were transplanted into a patient with Parkinson’s at Skåne University Hospital, Sweden [24]. This marks an important milestone for all stem cell research, with the transplantation of the nerve cells being performed perfectly, shown by magnetic resonance imaging (MRI) [24]. 


The STEM - PD trial at Lund University (The first in-human trial to test the safety of stem cells for Parkinsons) is continuing to replace lost dopamine cells with healthy ones, manufactured from embryonic stem cells [24]. Parkinson's disease slowly affects the nervous system, due to the loss of nerve cells in the substantia nigra in the brain. Nerve cells are crucial for the production of dopamine, so the implantation of nerve cells helps regulate brain activity and function by secreting regular levels of dopamine. STEM - PD aims to move from their first human trial all the way to global treatment around the world [24]. This latest success in the use of embryonic stem cells further pushes researchers around the world, with stem cells soon to unlock cures for multiple diseases, in addition to aiding with the worldwide shortage of organs. 


In Early 2023, researchers were able to differentiate neurons from induced pluripotent stem cells (iPSCs) [25]. The usage of iPSCs made it an arduous task, with the team needing to firstly differentiate the iPSCs into motor neurons, before placing them into coatings of synthetic nanofibers containing rapidly moving dancing molecules [25]. These mature neurons help aid the body’s nervous system, through sending rapid electrical signals around our body through tiny structures known as nerves. Within the near future, researchers believe that these mature neurons can be transplanted into those suffering with spinal cord injuries as well as neurodegenerative diseases (ALS, Parkinsons, Alzheimer's, Sclerosis) [25]. This new advancement in the usage of iPSCs allows scientists to research ethically sound ways of using stem cells for the treatment of all diseases.


Conclusion

Use of stem cells in repairing damaged cells/tissues, research into understanding diseases and testing for new drugs gives them incredible value in research and regenerative medicine. As the research for regenerative medicine improves, the success rate in the use of stem cells will gradually grow, which will hopefully loosen the tight legal grasp over the use of ESC (embryonic stem cells) and iPSCs due to their ethical problems (As seen in the table above), in either destroying and embryo or theoretically being from an embryo in iPSCs as they can be derived into an embryo. 

Researcher and scientists should strive to refine existing stem cell formation techniques, and through the difficult legal ties, battle their way to the final aim of having stem cells with the ability to differentiate into any cell needed to cure any disease, form any organs to be used in transplants, and research into greater depth the difficulty in battling certain diseases. 


References

[1] Weintraub, Karen. “20 Years after Dolly the Sheep Led the Way-Where Is Cloning Now?” Scientific American, July 1, 2016. 

[2] “The Life of Dolly.” Dolly the Sheep. Accessed November 26, 2023.

[3] “Dolly and Polly.” Encyclopedia Britannica. Accessed November 26, 2023.

[4] Natural World 5 min read. “Dolly the Sheep.” National Museums Scotland. Accessed November 26, 2023. 

[5] “Human Cloning.” ScienceDaily. Accessed November 26, 2023.

[6] “Somatic Cell Nuclear Transfer.” Somatic_cell_nuclear_transfer. Accessed November 26, 2023.

[7] “Therapeutic Cloning.” Therapeutic Cloning - an overview | ScienceDirect Topics. Accessed November 26, 2023. 

[8] Watt, Fiona M, and Ryan R Driskell. “The Therapeutic Potential of Stem Cells.” Philosophical transactions of the Royal Society of London. Series B, Biological sciences, January 12, 2010.

[9] Ye, Lei, Cory Swingen, and Jianyi Zhang. “Induced Pluripotent Stem Cells and Their Potential for Basic and Clinical Sciences.” Current cardiology reviews, February 1, 2013. 

[10] Ghaedi, Mahboobe, and Laura E Niklason. “Human Pluripotent Stem Cells (Ipsc) Generation, Culture, and Differentiation to Lung Progenitor Cells.” Methods in molecular biology (Clifton, N.J.), 2019. 

[11] “Why IPSC Research Is so Important (and so Tough).” Tecan. Accessed November 27, 2023.

[12] Lowden, Olivia. Advantages and disadvantages of induced pluripotent stem cells, November 10, 2023. 

[13] “Examining the Ethics of Embryonic Stem Cell Research.” Harvard Stem Cell Institute (HSCI). Accessed November 28, 2023. 

[14] Lenzer, Jeanne. “Bush Says He Will Veto Stem Cell Funding, despite Vote in Favour in Congress.” BMJ (Clinical research ed.), June 16, 2007. 

[15] Stem cell policy: World stem cell map. (Image: William Hoffman, MBBNet) Accessed November 29, 2023.

[16] Lachmann, P. “Stem Cell Research--Why Is It Regarded as a Threat? An Investigation of the Economic and Ethical Arguments Made against Research with Human Embryonic Stem Cells.” EMBO reports, March 2001. 

[17] Stem cell processing, Cellular and Molecular Therapies - NHS Blood and Transplant. Accessed November 29, 2023.

[18] Stem Cell Program, Pluripotent Stem Cell Research. Accessed November 29, 2023.

[19] Beford Research Foundation. ‘What are Induced Pluripotent Stem Cells? (iPS Cells)’ Apr 23, 2011

[20] Dana G. ‘Reflecting on the Discovery of the Decade: Induced Pluripotent Stem Cells.’ Accessed November 29, 2023.

‌[21] Cade Hildreth. Induced Pluripotent Stem Cell (iPS Cell) Applications in 2023. Accessed December 3, 2023.

[22] Clopton, David. n.d. “Graft versus Host Disease | Radiology Reference Article | Radiopaedia.org.” Radiopaedia. 

[23] Dr. Surat, and Dr. Tomislav Mestrovic. Induced Pluripotent Stem (iPS) Cells: Discovery, Advantages and CRISPR Cas9 Gene Editing. Accessed December 3, 2023.

[24] First patient receives milestone stem cell-based transplant for Parkinson’s Disease. Feb 28, 2023

[25] Amanda Morris. Mature ‘lab grown’ neurons hold promise for neurodegenerative disease. Jan 12, 2023

[26] University of Nebraska Medical Center. STEM CELLS. Accessed December 5, 2023

[27] Michael S. Pepper, C Gouveia. Legislation governing pluripotent stem cells in South Africa. (Image: Melodie Labuschaigne), Sept 2015



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