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Jake Holland 17641569

Stem Cell Therapy- Ethics and Future Development

Introduction Cancer is a leading cause of death within developing and developed countries, due to a growing and aging population is causing an increasing burden on medical services around the world (Zhang et al., 2017). There are a number of highly effective treatments available, however, these treatments have negative effects on both vital non-tumour tissues and functions which restrict the dose that can be administered to patients (Corsten and Shah, 2008). The disadvantages of the current therapies are the insufficient markers and their lack of specificity to tumour sites results in suboptimal efficacy, therapy resistance and subsequent tumour recurrence. Stem cell therapy may be able to increase the therapeutic efficacy of other treatments due to its ability to target tumours with greater specificity and reduce off-target events (Chu et al., 2020). Because of this it is important to evaluate the current methods we use to treat cancers; how effective these treatments are; the ethical concerns in using stem cells to treat patients and what future advancements we can make in different areas that could result in promising new treatments and better outcomes for patients.

Stem Cell Differentiation Stem cells can be differentiated into three main categories: embryonic, germinal, and somatic. Embryonic stem cells (ESCs) originate from the inner cell mass of the blastocyst and can renew indefinitely due to their high telomerase activity (Soltysova, Altanerova and Altaner, 2005). Germinal stem cells are derived from the primary germinal layers of an embryo. They differentiate into progenitor cells to produce specific organ cells. Somatic or adult stem cells are progenitor cells as they are less totipotent (Figure 1). They exist in the mature tissues such as haematopoietic, neural, gastrointestinal and mesenchymal tissues (Sagar et al., 2007). Adult stem cells (ASCs) are lineage-restricted (multipotent) in terms of their ability to differentiate and are referred to by their tissue of origin (e.g. mesenchymal stem cells, hematopoietic stem cells, neural stem cells). To overcome the limitation of ASCs as a multipotent cell they can be reprogrammed in induced pluripotent stem cells (iPSCs) using a specific set of transcription factors which allows them to regain their pluripotency, which may increase their therapeutic potential (Nawab et al., 2019a).

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Figure 1. Flowchart of the different stages of stem cell differentiation- The hierarchy of the different stem cells as you head lower down the hierarchy the cells lose potency and become more differentiated. (Nawab et al., 2019b)

Stem Cell Therapy- Treatment Efficacy The development of therapy is still on going but there are a few techniques currently being used to treat different forms of cancer that could developed as effective treatments for the different kinds of leukaemia and other cancer. Mesenchymal stem cells (MSCs), haemopoietic stem cells (HSCs), muscle stem cells (MuSCs), and neural stem cells (NSCs) can convert to tissue types of other lineages, both within and across germ lines. Mesenchymal stem cells that has been derived from bone marrow seem to have the highest cell potency being able to differentiate into almost all cell types when implanted into early blastocytes and are easy to handle in vitro (Corsten and Shah, 2008). Acute myeloid leukaemia (AML) is characterised by a rapid increase in immature myeloid cells (blasts) within the bone marrow. Current therapies fail to eradicate blasts from the bone marrow are the major causes of AML progression and relapse. To treat haematological malignancies one of the best candidates could be using MSCs due to their ability to replace certain tissues including the loss of bone marrow during treatment of AML. The use of adipose tissue derived-MSCs seem to be the most effective in this regard (Fathi, Sanaat and Farahzadi, 2019) . It was found that in mice the infusion of adipose tissue derived-MSCs along with HSCs increased the long-term and short-term effect of haemopoietic reconstitution in patients undergoing radiotherapy. The effect appears to be linked to MSCs immunosuppressive effects which limit immune reaction between the host and donor cells. Another possibility is the ability of MSCs to secrete numerous cytokines and growth factors, which may increase the proliferation of engrafted HSCs. MSCs could also improve the honing of HSCs towards the

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niches of bone marrow (Fernández-García et al., 2015). The accumulative effect of these factors may improve the therapeutic effect of hematopoietic grafts in patients with AML. Another study showed that the addition of MSCs can also be useful for cell therapy by using them as a vehicle for delivering anti-tumour molecules into the tumour microenvironment. Due to the innate tropism and large quantities to be collected in a less invasive and easier manner in adipose tissue derived-MSCs (AT-MSCs) compared to other MSCs. Cytokine interferon-beta (IFN-β) has been shown to have inhibiting effects on both tumour growth and angiogenesis (Ahn et al., 2013). It has also been shown that MSCs genetically engineered to secrete IFN-β contribute potent pro-apoptotic effects and are capable of inhibiting both tumour growth and angiogenesis (Chawla-Sarkar, Leaman and Borden, 2001). The Ahn et al 2013 study investigated whether the use of IFN-β secreting AT-MSCs can result in a greater reduction of the tumour burden within canines. The study showed that AT-MSCs could be engineered to secrete IFN-β and was able to selectively engraft on melanoma tissue which significantly tumour burden within animals. It also showed the ability for AT-MSCs to be able to migrate towards tumours in vitro and in vivo however this doesn’t seem to be because of genetic modification or the expression IFN-β. This study was able to demonstrate the effectiveness of treatment using both MSCs and chemotherapy (Ahn et al., 2013). While AT-MSCs show an increase in efficacy compared to stem cells derived from other tissues, it is also important to consider other types of stem cells that may be more effectual. HSCs are found in the bone marrow and were originally used as a treatment for irradiation and in animal models was found to be effective in averting death. Although, marrow that was not genetically identical to the recipient resulted in an immunological reaction which caused inflammation, termed graft-versus-host disease (GVHD) (Copelan, 2006). The use of HSCs for the generation and regeneration of blood-forming and immune systems. HSCs have been vital in bone-marrow transplantation which have been used in extensively in therapeutic settings. Further to this, studies have found that bone marrow and purified HSCs, can give rise to non-haemopoietic tissue suggests that these cells have more differentiation potential than previously thought. Further studies are needed to analyse the future potential of this plasticity and whether the use of HSCs could open a new frontier for their use (Reya et al., 2001). There is still significant morbidity and mortality associated with haemopoietic stem cell transplantation (HSCT) and is a high-cost, highly specialised medicine. It requires a significant amount of infrastructure and other specialists from various fields of medicine. However, in some instances HSCT is o limited to countries abundant in resources and may represent the most cost-effective treatment in some countries. While HSCTs were used for a variety of treatment, the most common allogenic HSCT used was to treat acute lymphoid leukaemia and bone marrow failure while the most frequent indicator of an autologous HSCT was a plasma cell disorder. These treatments tend to happen more frequently in countries with higher government health expenditure, higher gross national income per capita and greater amount of available transfer teams. The combination of these factors would indicate that this kind of therapy is still most accessible in countries that have access to better material conditions can more effectively use HSCT as a treatment due to it being an expensive procedure (Gratwohl, 2010). This could indicate

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that further advancements in the development of this treatment may be necessary for it to become more accessible for to countries of a lower economic status. There are other government economic policies, such as, tariffs that impose price increases on drugs that are imported into more developing countries. There are also certain cultural differences that impact a patient’s ability to acquire ideal treatment options for a disease. Chinese doctors pointed out to western physicians that eight months of chemotherapy may be prohibitively expensive for patients living in a worker’s commune away from a city with access to chemotherapy. However, as China has developed economically this is unlikely to be such a problem now but for other developing countries this criticism is worth considering for treatment options (Gajewski and Robinson, 2007).

Stem Cell Therapy- Ethical Considerations Some of the issues around the use of stem cells involves an ethical discussion on where they come from and process involved in their collection. While there are sources of stem cells that don’t cause an ethical dilemma, at least in their collection, such as, adult stem or umbilical cord blood, the focus of this section will be on the controversial collection of stem cells that involves a human embryo. An important factor is first determining how to define an embryo, politically this is defined in many countries in Europe including, The Netherland, Belgium and Germany which defined an embryo based on whether it has the potential to become a human life. This idea of the potentiality of life has become more and more embraced including the Oliver Brüstle vs Greenpeace case where the Court of Justice of the European Union that removed the stipulation that the embryo had to be fertilised and that it only had to have the potentiality to grow into a human being. However, this definition is still highly debated and has not become the agreed upon definition by everyone in the scientific community (de Miguel Beriain, 2014). The main ethical issue is the use of ESCs that are obtained from embryo’s which are destroyed after the stem cells have been collected. This is the main source of contention for people that believe an embryo is a human life and gives that life moral consideration as this would be equivalent to murder in their eyes. This is usually because they believe that using human life as a means to conduct research is immoral and that an embryo is worthy of the same consideration as a fully developed human. This stands in stark comparison of others who do not believe that an embryo is worthy of moral consideration or that any harm done to the embryo is justified due to the ends that researchers are tying to reach. Devolder and Savulescu argue that the use of embryonic cells has led to many developments within the field and could lead to the further discovery of treatments if allowed to continue. They also point out that cloning of embryonic tissues could solve problems of, transplantation tissue shortages, issues with compatibility during transplantation and the expansion of transplantations to include repairing damage from strokes and heart attacks. On the ethics side they argue that the delay in using stem cell therapy that could be used to save lives currently and, in the future, could result in the deaths of future patients. This, in their eyes, would be the same as killing hundreds of thousands if not millions of people (Devolder and Savulescu, 2005). The argument being made is that action and inaction that result in the deaths of people are both equally wrong and people should be held to account for the result of their inaction. The debate on the ethics of using stem cells is extensive and is also ongoing but when

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considering the practices of medicine, it is important to understand the bioethics of the choices we choose to make. Richard Feynman received the Nobel prize for physics in 1965 and he also helped develop the first atomic bomb at Los Alamos, in his book “The Meaning Of It All” he wrote “Is science of any value? I think a power to do something is of value.” He goes on to elaborate by talking about keys, everything we discover in science or invent is a key “to the gates of heaven” but the same key will also open “the gates to hell”. His overall message is that science doesn’t tell us how to use keys it finds them or predicts them, how we use keys is up to us. As with stem cells it is possible it can be used to cure many diseases and help lots of people, but people have some valid concerns that this will lead humanity off an “ethical cliff” that could result in a lot of once clearly drawn lines becoming more blurred (Devolder and Savulescu, 2005).

Conclusion While our current research does show a positive direction for the research of stem cells there still needs to be more research into the potentiality of some stem cells in the hopes that the options for their possible treatments can be increased. Also, it is important that continued research into the efficacy of different types of stem cells and the pros and cons of using different types are weighed up with the patient outcomes being at the forefront of consideration. Along with this the ethical considerations of using stem cells for research or treatment are considered fully and discussed within academia and also the general public so they are informed of all the current discussions so we do not alienate people away from the sciences and keep people engaged.

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Devolder, K. and Savulescu, J. (2005). The Moral Imperative to Conduct Embryonic Stem Cell and Cloning Research. Cambridge Quarterly of Healthcare Ethics, 15(01). Fathi, E., Sanaat, Z. and Farahzadi, R. (2019). Mesenchymal stem cells in acute myeloid leukemia: a focus on mechanisms involved and therapeutic concepts. Blood Research, [online] 54(3), p.165. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779935/ [Accessed 23 Mar. 2020]. Fernández-García, M., Yañez, R.M., Sánchez-Domínguez, R., Hernando-Rodriguez, M., PecesBarba, M., Herrera, G., O’Connor, J.E., Segovia, J.C., Bueren, J.A. and Lamana, M.L. (2015). Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model. Stem Cell Research & Therapy, 6(1). Feynman, R.P. (1998). The meaning of it all : thoughts of a citizen scientist. Reading: Persues Books, Cop. Gajewski, J.L. and Robinson, P. (2007). Do affluent societies have the only options for the best therapy? Leukemia, 21(3), pp.387–388. Gratwohl, A. (2010). Hematopoietic Stem Cell TransplantationA Global Perspective. JAMA, [online] 303(16), p.1617. Available at: https://jamanetwork.com/journals/jama/fullarticle/185756 [Accessed 3 Apr. 2020]. de Miguel Beriain, I. (2014). What is a human embryo? A new piece in the bioethics puzzle. Croatian Medical Journal, [online] 55(6), pp.669–671. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295065/ [Accessed 7 Apr. 2020]. de Miguel-Beriain, I. (2015). The ethics of stem cells revisited. Advanced Drug Delivery Reviews, [online] 82–83, pp.176–180. Available at: https://www.sciencedirect.com/science/article/pii/S0169409X14002749?via%3Dihub [Accessed 6 Apr. 2020]. Nawab, K., Bhere, D., Bommarito, A., Mufti, M. and Naeem, A. (2019a). Stem Cell Therapies: A Way to Promising Cures. Cureus, 11(9). Nawab, K., Bhere, D., Bommarito, A., Mufti, M. and Naeem, A. (2019b). Various stages of stem cell differentiation. Cureus. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823091/figure/FIG1/ [Accessed 25 Mar. 2020]. Reya, T., Morrison, S.J., Clarke, M.F. and Weissman, I.L. (2001). Stem cells, cancer, and cancer stem cells. Nature, [online] 414(6859), pp.105–111. Available at: https://www.nature.com/articles/35102167 [Accessed 2 Apr. 2020]. Sagar, J., Chaib, B., Sales, K., Winslet, M. and Seifalian, A. (2007). Role of stem cells in cancer therapy and cancer stem cells: a review. Cancer Cell International, 7(1), p.9. Soltysova, A., Altanerova, V. and Altaner, C. (2005). Cancer stem cells. Neoplasm, 52(6), pp.435–440.

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Zhang, C.-L., Huang, T., Wu, B.-L., He, W.-X. and Liu, D. (2017). Stem cells in cancer therapy: opportunities and challenges. Oncotarget, [online] 8(43). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650462/....