In simple terms, stem cells are the cells found in the body that are special for 2 different reasons. First, they are able to replicate themselves, creating new cells alike by passing over their DNA during the division process known as mitosis. Second, they have the ability to differentiate, that is, specialise themselves for a more precise function in the body, thus developing into different tissues. Stem cells are widely spread throughout the body, given that they have essential roles in tissue maintenance and repair after injury. A concrete example would be the hematopoietic stem cells located in the bone marrow, which can develop into the cells that make up about 45% of the blood (red cells, white cells, and platelets).

Many types of stem cells exist, the most versatile of them being embryonic stem cells, since they can differentiate into all the cells needed by the growing foetus. For this reason, embryonic stem cell research is vastly performed by scientists around the world, in hopes to better understand and cure various devastating diseases, such as Parkinson’s, Alzheimer’s, diabetes, as well as certain types of cancers, namely leukemia and lymphoma. Scientists believe that, by closely observing the way stem cells mature into various tissues, they will be able to understand in depth how diseases develop. Moreover, by controlling the differentiation process of stem cells, researchers strive to create new and healthy tissue, fit for replacing the one that has been damaged due to a certain illness (for instance, the replacement of dead neurons, in order to cure Parkinson’s disease). The main types of stem cells, which are the subject of ongoing global research, are embryonic stem cells, adult stem cells, and induced pluripotent stem cells.

Embryonic stem cells emerge inside blastocysts (embryos that are between 3 and 5 days old), which contain about 150 cells in total. These are pluripotent stem cells, which means that they are able to divide into more stem cells or to differentiate into any type of cell in the body. This outstanding ability makes embryonic stem cells crucial for regenerating or repairing damaged tissue and organs.

Adult stem cells (also referred to as somatic stem cells) are undifferentiated cells identified in small amounts throughout many tissues of the adult organism. Their role is to maintain tissue homeostasis, that is, keeping the internal environment of the body stable, and to replace cells that have gone through apoptosis (programmed cell death), necrosis (premature cell death, caused by lack of blood flow to the tissue where the cell resides), or other types of cell death, though in a more limited manner compared to embryonic stem cells. Unlike the pluripotent cells, adult stem cells are defined as either multipotent, possessing less differentiation potential, or as unipotent, only able to generate a single specialised cell type. Somatic stem cells can be classified, depending on their origin and differentiation potential, into hematopoietic stem cells and mesenchymal stem cells. The former are predominantly found in bone marrow, umbilical cord blood and peripheral blood (the blood that travels through the heart, arteries, capillaries, and veins) and are able to become various blood cells, as mentioned earlier. The latter are generally found in tissues like bone marrow, adipose tissue, umbilical cord and dental pulp, and are capable of differentiating into various mesenchymal tissue cells, including bone, adipose and cartilage.

Induced pluripotent stem cells are adult stem cells which have been genetically modified to resemble embryonic stem cells as much as possible, in regard to their differentiation potential. This method serves as a bypass to the ethical controversies surrounding the research of embryonic stem cells, which will be talked about in detail further in the study.

How do stem cells actually work?

The base mechanism behind stem cell differentiation is represented by the activation of specific genes and the repression of others, which influence the size, shape, function, and metabolic activity of the cell. This fascinating process occurs thanks to a combination of both genetic and environmental factors: complex signaling pathways, which are conducted by growth factors (naturally occurring proteins), cytokines (proteins which are either secreted by immune cells or have the role of chemical messengers), and epigenetic alterations, such as DNA methylation (the process in which a methyl group attaches to a DNA molecule, usually to the cytosine base) and chromatin remodeling; the microenvironment surrounding the stem cells, any change occurring in it having a direct effect on the culture conditions in vitro, therefore controlling the direction of differentiation; physical and mechanical forces, cell-to-cell contacts and the geometry of the extracellular matrix (the area in-between the cells, mainly composed of structural proteins like collagen and elastin, aimed to provide structural support and other essential functions, including cell adhesion and migration); directed differentiation in research, during which scientists control the environment where stem cells develop, thus being able to achieve the specific cell types they are seeking.

Having discussed the main factors which have the potential to govern cell differentiation, the actual shifts that cells must undergo are just as complex: alternations in cell morphology, that is, changes in the shape of the cell; changes in membrane potential, which lie at the base of the cell’s ability to respond to signals and perform the functions it is designed for; metabolic activity modification (the adaptation of the cell’s means of using up and producing its own energy to better fit into its new role); shifts in sensitivity to certain external factors, which guide the cell in the process of maturing and adapting to its new function in the body.

What is stem cell research?

In its general sense, stem cell research is a scientific investigation conducted with the ultimate goal of using stem cells in the development of therapies which may repair or replace damaged cells and tissues, thus holding the potential to tackle a number of different diseases, such as cancer, heart disease, diabetes, and neurodegenerative conditions, like Parkinson’s and Alzheimer’s.

This process involves isolating and creating cultures of stem cells, advancements like induced pluripotent stem cells being of great help, since they represent adult stem cells which have been genetically modified to resemble and to have similar properties to embryonic stem cells, undergoing a “regression” of sorts. Utilising this sort of stem cells enables researchers to bypass the controversies of obtaining embryonic stem cells directly from human embryos, which are damaged as a result.

In order to isolate stem cells, scientists must transfer the internal cell mass of a blastocyst (a hollow sphere of cells, that forms a few days after the fertilisation of an egg) into a specific medium in a laboratory dish. This medium, known as the culture medium, is made up of nutrients that encourage the growth and division of cells. Culturing of stem cells is not always successful, but, when the cells do manage to grow and multiply continuously, they are further spread across other different culture dishes, process known as subculturing, with the aim to obtain millions of copies (clones) of the same cell, that can then serve research purposes.

Among the two main types of stem cells, embryonic and adult, the former are the easiest to culture and often have the ability to maintain their state for months, keeping their pluripotent properties and forming, in large amounts, the embryonic stem cell line. These cells can then be frozen, stopping its metabolic cycle in order to prevent it from differentiating, and sent to various laboratories for extended research. In contrast, culturing somatic stem cells is more difficult, as they can proliferate only for a limited period of time. They must first be identified as cells that are able to multiply through mitosis, forming genetically identical daughter cells, which then have the ability to differentiate into all the specific cell types of their designated tissue. After their identification, adult stem cells can be utilised to regenerate the damaged cells in their specific tissue, an example being the first success in adult stem cell research, namely the bone marrow transplant, used to treat several blood-related conditions, such as leukemia and sickle cell anemia.

What is the history of stem cell research?

The study of embryonic stem cells (ES cells) began in 1981, when British scientists Martin Evans and Matthew Kaufman discovered methods to obtain embryonic stem cells from mouse embryos. However, since these develop and evolve in a significantly different way compared to human embryos, researchers began to seek ways to isolate human embryonic stem cells, which led to the discovery of a way to derive stem cells from human embryos donated by fertility clinics, in 1998. James Thomson and his team from the University of Wisconsin are responsible for this breakthrough, which lead to countless other advancements in this field, as of today.

Harvesting embryonic stem cells from already existing human embryos is only one of the two possible pathways. Its counterpart involves using cloned embryos, obtained through a technique called somatic cell nuclear transfer (SCNT), which emerged in 1996, with the Scottish scientist Ian Wilmut successfully cloning Dolly the sheep. An adult cell from a sheep’s udder (mammary gland) was taken and left to divide. Then, after its successful proliferation, one of the daughter udder cells had its nucleus extracted and placed next to an egg cell from a second sheep, which had had its nucleus previously removed, and the two were fused together through an electrical shock. The resulting egg cell, containing the genetic material of the first sheep, multiplied until it became an embryo, which was, in the end, placed inside a third sheep, the surrogate mother. After five months, this sheep gave birth to Dolly, who was genetically identical to the first sheep, which had provided the udder cell. Human embryos can be cloned in a similar manner, by fusing the nucleus of a donor’s adult cell, which contains their DNA, with an enucleated egg cell, which is stimulated to begin dividing and growing into an embryo as a result. Since this newly formed embryo was made using the donor’s DNA, the stem cells harvested from it are highly likely to be compatible with said donor, therefore reducing the risk of their body rejecting the new tissue that was formed after the stem cells have differentiated. While SCNT is actively used as a core part of stem cell research in more permissive countries like South Korea, therapeutic cloning is generally banned in Germany and Romania, being viewed as a violation of a human’s dignity and right to life.

 

Previously in the article, induced pluripotent stem cells have been described as somatic stem cells which have been genetically modified and brought to an embryonic-like state, which provides them with the ability to differentiate into almost all types of cells found in the human body, instead of their potential being limited to only a few categories of cells. With this being said, the technique required to achieve this was not always known, the first induced pluripotent mouse stem cells being created by the Japanese scientist Shinya Yamanaka and his team at Kyoto University in 2006. The first induced pluripotent human stem cells were created in 2007, by James Thomson’s team. They managed to turn human adult skin cells into pluripotent stem cells, through the insertion of an adenovirus into the somatic cells. As is also the case with SCNT, the pluripotent stem cells obtained are theoretically compatible with the donor’s organism. Back in the day, scientists were uncertain of the safety of these induced pluripotent stem cells, as the virus used for genetic reprogramming might cause mutations that could lead to cancer in patients, for instance. However, the process has since been refined and, as of today, induced pluripotent stem cells are already being tested in clinical trials. If proven highly efficient in treating patients, this method has the potential to eradicate the need for SCNT in stem cell harvesting.

How did stem cell research emerge in Romania, Germany and South Korea?

In Romania, the history of biological research began in 1970, when Professors Nicolae Simionescu and Maya Simionescu sprouted a genius idea from the seeds of their creativity and aspiration for the future of Romanian science: a research center for cell biology and pathology in Romania. From that point onwards, efforts have been made to create an institution in Romania that is well-equipped with adequate machinery and bright minds ready to work together, with the common aim to better understand the biology of cells and to treat diseases using newfound knowledge. In the year 1979, the Inauguration of the Institute of Cellular Biology and Pathology (ICBP) “Nicolae Simionescu” took place, fulfilling the dreams of the founding researchers and welcoming Nobel Prize Laureates like George Palade and Christian de Duve and influential Professors, such as David Sabatini and Werner Franke.

It was not until 2007, however, that stem cell research started to emerge within Romanian laboratories, the marking point being the International Symposium “Stem Cells as therapeutic alternative”, organised by the ICBP, which was then followed by other international symposiums and workshops exploring the potential of stem cells. This eventually led to the first successful haploidentical stem cell transplant (transplant using hematopoietic cells from a donor that is a half-match for the recipient) in Romania, performed in 2015 on a 33-year-old woman with Hodgkin’s lymphoma. The donor was the mother of the patient, a 57-year-old woman with 8/10 human leukocyte antigen compatibility. This represented a milestone in Romania’s healthcare system, opening doors for the potential and development of stem cell research and treatment in the country.

Germany is the country where the term “stem cells” has its very origins, coined by Ernst Haeckel, a professor of zoology, in his published lectures on “Natürliche Schöpfungsgeschichte”¹ (1868), where he used the word Stammzellen² (stem cells) to refer to protozoa (unicellular organisms), as he believed that they were the ancestors of multicellular organisms, which had ultimately evolved from the first and most rudimentary forms of life, the Monera (archaea and bacteria). In 1877, he applied the concept of stem cells to ontogeny (the development of a living organism from conception to death), utilising the term Stammzelle (singular form of Stammzellen) to describe the zygote as the origin from which all the other cells of an animal or human organism emerge.

The first successful stem cell transplant performed in Germany happened a long time before modern research became a common practice in the country. Sebastian Gärtner, a man suffering from a form of blood cancer, was the first patient in Germany to receive a stem cell transplant from his own blood, at Heidelberg, in 1985. Even though Germany is, in a way, the birthplace of the notion of stem cells as we know it today, strict laws have been enforced, which have highly limited the work of researchers, such as the German Embryo Protection Act of 1990, which banned the production of embryonic stem cells in the country. Modern stem cell research started in the year 2002, after the so-called “Embryonic Stem Cell Act” took effect, permitting the regulated import of isolated embryonic stem cells for research purposes.

In South Korea, stem cell research became a major point of interest in the scientific field in the year 2004, when Hwang Woo-Suk, a veterinary scientist, claimed that he and his team had managed to acquire the first human embryonic stem cell line using the SCNT technique, which has been discussed earlier in the paper, on human embryos, allegedly requiring 242 human eggs for the. One year later, the veterinarian allegedly stated that 11 patient-specific stem cell lines have been created with 185 human eggs, which posed no concern regarding their rejection by the patients’ bodies. However, this represented only the beginning of the so-called Hwang Scandal, all of Hwang’s 11 alleged human stem cell lines proving to be fake, according to the investigation conducted by the Seoul National University, which ended on December 29, 2005.

Moreover, studies have suggested that Hwang had acquired human eggs unethically, purchasing human eggs and forcing his female research associated to donate their own eggs. Amidst this social and scientific feud, significant breakthroughs in the field of stem cells have occurred in South Korea, such as Hwang Mi-Soon’s successful transplant of multipotent adult stem cells isolated from umbilical cord blood. The recipient of the cells, who was 37 years old at the time, had suffered a spinal cord injury that had confined her to a wheelchair for over 19 years, but she thankfully managed to recover. Not much time after Hwang Mi-Soon’s transplant, Korea’s Bioethics and Biosafety Act was enforced, which, in short, banned human cloning and the production of new embryos for any purposes excluding pregnancy, and only allowed research to be conducted on pre-existing embryos, additional regulations applying to those that had been stored for over 5 years.

Why is stem cell research ethically controversial, and what other challenges does it face?

The core of the ethical controversy that has surrounded stem cell research, ever since the first successful harvesting of human embryonic stem cells in 1998, lies in the general perception of the human embryo itself. As has been previously mentioned, new human embryonic stem cells can only be obtained using human embryos, which unfortunately are destroyed in the process, no matter whether they were pre-existing or cloned through SCNT. Therefore, people’s decision to advocate for or against stem cell research is mostly dependent on their view of the human embryo, which can be stretched along a wide spectrum. Should an embryo be granted the same rights and protection as a fully developed human simply because it exists, or should it be viewed as resourceful research material, since it is too rudimentary to encompass the true meaning of a human life? This question has been debated for decades, and, while there are individuals who position themselves at either one of the far ends of the spectrum, some people’s mindset falls somewhere in-between.

First of all, there are the ones who support the idea that the full value of a human life can be found even in its earliest form, i.e. the embryo, and they therefore suggest that any activity performed on human embryos must abide by the same guidelines and rights that apply to any completely developed human. In other words, they believe that the legal and ethical implications of experimentation conducted on embryos should be considered the same as those appliable to the hypothetical research done on newborns, for instance, who have no power of consent whatsoever. These people further think that research can be performed within moral grounds only if it is in the best interest of and causes little to no harm to the subjected being, in this case, the embryo. According to this view, embryonic stem cell research is undoubtedly unethical and represents a violation of basic human rights and safety, as the embryo is damaged in the process, this being the equivalent of a human life being ruthlessly taken.

Second of all, there are the people who share the polar opposite belief. They argue that an embryo is merely a primitive form of early human life, that only has the uncertain potential of becoming a fully developed person after a set period of time (not all embryos fully develop, several dying before or not long after implantation, or even in the later stages of pregnancy), and that it is therefore not eligible to be treated equally to a grown individual, which is provided with rights, autonomy and protection. According to this way of thinking, using embryos as essential elements in research is morally acceptable, as the embryo itself is perceived as nothing more than a cluster of cells which, if studied carefully, may lead to meaningful breakthroughs. This perception can do as much as impose a moral responsibility towards research conducted on embryos, given the vast array of benefits that it may bring in favour of humanity.

Third of all, some people might as well position themselves somewhere in-between the two philosophies surrounding embryos, borrowing and balancing elements from both. They reinforce the idea that a human embryo’s status as a person with rights and autonomy increases as the embryo develops, therefore suggesting that experimentation using early embryos, in favour of the humankind, is ethically reasonable. This implies that a threshold exists, namely a certain point in the growth of an embryo after which it is to be treated with the same level of respect as any other person, making their destruction for research purposes no longer morally acceptable. In the case of many nations, this threshold has become a standardised period of 14 days, which roughly aligns with “the emergence of the primitive streak that marks the beginning of individuation (the embryo is no longer able to twin) and the completion of implantation (14 days after fertilisation)” ³.

Another point of concern regarding the ethics of stem cell research is the acquisition of human embryos. Needless to say, the means through which scientists obtain the embryos required for their work greatly impact the morality of their research. Widely accepted ways of acquiring embryos include the surplus of IVF (in vitro fertilisation), alongside strict regulations regarding full, written consent of and transparency towards the donor, and ethically guided SCNT. Under no circumstances is it acceptable nor legal to obtain human embryos, eggs or sperm (embryos ultimately result after the sperm cell comes into contact with the ovum) by overlooking any of the guidelines mentioned, as it was the case with Dr. Hwang, who allegedly forced his female research colleagues to donate their egg cells and purchased ova.

In addition to the ethical challenges that stem cell research tackles, there are other problems that arise in this field, as well as in the clinical applicability of stem cells. Embryonic stem cell’s ability to multiply indefinitely, in their undifferentiated phase, can cause their hyperproliferation, which may lead to benign tumours and, in severe cases, to cancer. In contrast, adult stem cells proliferate much more slowly and are exceptionally tricky to maintain undifferentiated in cultures. Embryonic stem cells usually differentiate sporadically, forming multiple types of specialised cells and hardly ever a culture of a singular cell type. Even though the purpose of culturing embryonic stem cells is to ensure, as much as possible, that their differentiation is uniform and results in one cell type, through controlling their proliferation environment, the required techniques are difficult, and the perfect combination of factors, that guarantees the successful culture of a singular cell type, is not yet known. Several such factors are not substances that may simply be added to the culture medium and include “mechanical tension, large-scale electric fields, or complex structural environments provided by the cells’ embryonic neighbours in order to activate appropriate genes and maintain normal gene expression patterns” ⁴. As opposed to induced pluripotent stem cells and embryonic stem cells obtained through SCNT, ES cells which come from new embryos pose the risk of being identifiable by the body’s immune system, because some contain HLAs (human leukocyte markers), such as MHC (major histocompatibility complex) class I. Because of this, in the case of transplants or clinical trials performed using this type of stem cells, immunity suppressors, the efficiency of which is not certain, should be used. The high cost of stem cell treatments should also be taken into account, as there are limited, but costly approved therapies that are past their experimental phase (they will be discussed in more detail further in the study).

What is the public attitude towards stem cells in Romania, Germany and South Korea?

Regarding Romania, a survey has been conducted in 2015, assessing the opinions of younger and older physicians towards stem cell research. More specifically, the subjects gave their answers to 6 different questions. Can a couple conceive a child with the purpose to collect stem cells needed for the bone marrow transplant of a pre-existing child, who suffers from a blood condition? With a mean of 6.37, moderate agreement has been shown for this action, a relatively high number of Romanian physicians finding it ethically acceptable if it can ultimately save a life, but opinions varied, the standard deviation being 3.7. Should using stem cells that come from adults be allowed? The majority of physicians have had positive answers to this question, the mean being 7.78. Should creating embryos for stem cell harvesting be allowed? This question received the lowest agreement, with a mean of 2.00, most physicians believing that this action is not ethically acceptable, most likely having a perception on human embryos which falls into the first category discussed in the previous section; older physicians have shown less support for this idea, compared to younger ones. Should the collection of stem cells from aborted embryos be allowed? The answers for this question have shown mixed opinions, with a standard deviation of 4.2 and a mean of 4.95; overall, moderate agreement has been expressed, and older physicians accepted this idea more easily than younger physicians. Should the obtaining of stem cells from embryos created through SCNT be allowed? With a mean of 3.24, this item has shown the second most negative response, most physicians disapproving of this action; however, there were more younger physicians who agreed with this idea, compared to the older ones. Should the harvesting of cord blood stem cells and their storage in a cell bank be allowed? This question has received almost universal positive responses, with a mean of 9.50 and a median of 10.00; almost all physicians agree that this action is both morally acceptable and highly beneficial.

In regard to Germany and South Korea, the results from a survey conducted in 2018 will be analysed. This was a multinational survey, with people from 6 countries answering various questions and expressing their views towards regenerative medicine and stem cell research. It is worth mentioning that regenerative medicine, the branch of medicine which focuses on regenerating and replacing damaged cells of various organs, heavily implies the use of stem cell treatments, alongside other techniques. The initiators of the survey collected 100 answers from each country included and publicly shared their findings.

The first question assessed people’s recognition of the terms iPSCs (induced pluripotent stem cells) and ESCs (embryonic stem cells; while 82.0% of Germans had some level of knowledge regarding ESCs, only 12.0% had heard about iPSCs. A similar trend can be observed with South Korea, 88.0% of people having an idea what ESCs are, whereas only 29.0% of South Koreans had heard of iPSCs; this is likely due to iPSCs being a more recent discovery, having emerged the scientific world in the yearly 2000s. However, the higher percentage of Koreans who were familiar with the term “induced pluripotent stem cells” might have been determined by South Koreas proximity to Japan (the birthplace of iPSCs).

The second question of the survey concerned people’s overall views on stem cell research. In Germany, as well as in South Korea, the most popular opinions were the following: “I think we should press ahead with regenerative medicine research” ⁵ (29.0% in South Korea and 44.0% in Germany) and “I have few concerns, but it’s inevitable that regenerative medicine research will be emphasised” ⁶ (61.0% in South Korea and 31.0% in Germany). People’s overall acceptance of the advancements in regenerative medicine research, along with the fact that, in both countries, the percentage of individuals who thought that research in this sector should be stopped was the lowest, indicates that the majority of Germans and South Koreans find regenerative medicine research, which also implies the study and culturing of stem cells, useful and, to a degree, ethically appropriate.

The third section inquired how much people trust the scientists who touch upon the safety and effects of regenerative medicine. In South Korea, only 6% of people fully trust the stories of experts, 42% of people only trust them to an extent, and 11% of the individuals relatively disagree with trusting the experts. These numbers emphasize Korean’s overall scepticism regarding the statements of scientist, which might be fuelled by the Hwang Scandal, since it caused people to lose faith in scientists working in this field. In the case of Germany, 29% of individuals fully agree with trusting scientists, 47% only partially agree, and as little as 4% relatively disagree, emphasising how most Germans view scientists as reliable.

The fourth question assessed the topics of interest of the people, regarding regenerative medicine, each person being able to choose three options from a list of 12. For both Germans and South Koreans, the topic which arose the most interest was the risk (about 60% of Germans and approximately 52% of South Koreans were interested in this topic). The second most opted for topic differed between the two countries. In the case of Germany, this was represented by the benefits (about 42%), while in South Korea, this was represented by the cost of treatment (approximately 43%). These imply that most people wish to know more about the risks that come with regenerative medicine, as it is a newer branch of medicine. However, extensive research and the constant implication of regulatory bodies aim to ensure that therapies are generally safe, before they are made available for patients.

The fifth section inquired about the factors that people take into consideration in order to accept regenerative medicine. Similarly to the previous question, the participants had to choose the 3 options that best represent their views, from a list of 10. The two most chosen factors in Germany (both at about 40%) were “whether society can prevent abuse and misuse by regulation” ⁷ and “credibility of executors of research activities such as university, government, companies, and so on” ⁸. In the case of South Korea, the most opted for factor was “whether experts can deal with risks and accidents” ⁹ (almost 50%), with the second most popular being “whether society can prevent abuse and misuse by regulation” ¹⁰ (about 44%); this factor seems to be the common ground between South Korea and Germany when it comes to accepting regenerative medicine, the people from both countries needing to make sure that regenerative medicine treatments, stem cell therapies included, can be administered with responsibility and in the best interest of the receiver, and that society is able to detect and prevent any practices that do not adhere to this principle.

What are the benefits of stem cell research? Do they outweigh the drawbacks?

In order to fully grasp whether the benefits of stem cell research outweigh the downsides or not, an in-depth look should be taken at all the possibilities that this field of scientific work brings.

Pluripotent stem cells give scientists an insightful view on how humans develop and how genes become expressed or repressed, guiding the formation of specific proteins and encouraging cell differentiation. Experts are aware that several conditions, like cancer and birth defects, arise from atypical cell division and specialisation. Therefore, by getting a grasp of how cells normally develop, researchers will be able to detect the abnormalities that give rise to such conditions, which usually have devastating effects on the affected people. Moreover, due to their ability to differentiate, stem cells pose the potential to generate the cells and tissues needed to replace the damaged ones, thus being able to treat diseases like cancer, diabetes, Parkinson’s, Alzheimer’s, and so on. In addition, stem cells could be used to create tissue banks compatible with a high number of recipients, providing enough transplant material for the  ever-growing number of patients and preventing the recipients’ bodies from rejecting the transplanted tissues. A potential candidate is represented by the stem cells from fallen baby teeth, as they are easy to isolate, they regenerate fast into solid tissues, and they would be compatible with close relatives of the donor.

Another benefit of stem cell research is somatic cell nuclear transfer (SCNT), which has been described earlier in the study. This process can be used to generate specialised cells that are capable to repair and regenerate damaged tissues and organs and that should, in theory, be compatible with the patient, as the genetic information, which is required to create the pluripotent stem cells that further differentiate, is taken from the nucleus of the patient’s own adult cells. Transplanting tissues obtained through SCNT would not imply the need for   immune-suppressing drugs, giving the patients a much higher survival chance.

There are therapies that may arise from the usage of somatic stem cells, transplantation being an example. If the biggest challenge surrounding adult stem cells could be overcome, that is, isolating them from all the tissues of the human body and manipulating them to multiply and differentiate according to the guidelines of normal cell function, they could then be reintroduced into the patient, eliminating the risk of a negative immune reaction. If successful, somatic stem cell therapies could also significantly decrease the need for ES cells, which are known for giving rise to controversy.

Last but not least, gene therapy has to be accounted for. If genetically altered, stem cells, or the specialised cells resulted from them, could be utilised as carriers of genetic material, in order to treat genetic conditions  characterised by missing or mutated genes.

Taking everything into consideration, it appears that the benefits of stem cell research do, in fact, outweigh the potential drawbacks. Although this area of research continues to be subject to intense ethical debate and health concerns, most therapies being in their experimental phase still, the promising opportunities it brings, including curing terminal illnesses and regenerating damaged organs are, in the views of many experts, worth fighting for. Only with careful and extensive research will stem cells be able to live up to their impressive potential, and for that, compromises must be made.

 What treatment options are and might be available?

Before diving into the innovatory treatments that stem cells have made possible, it is crucial to mention that stem cell treatments are unique to a certain illness and cell type, and they might be specific even to the patient in question. Anyone seeking these types of treatments is advised to take the necessary precautions when encountering clinics that advertise a singular stem cell treatment as efficient in treating a vast array of conditions that affect multiple areas within the body, as they may cause damage on a physical, psychological, and even financial level.

On one hand, there is only a handful of approved stem cell treatments as of today, that is, those whose efficiency and safety have been proven by extensive scientific evidence, and which are accepted and regulated by institutions such as the EMA (European Medicines Agency), the FDA (Food and Drug Administration) in the USA, and so on. An approved stem cell treatment by the FDA, which is also widely recognised as being safe and effective, is hematopoietic stem cell transplantation (bone marrow/blood stem cell transplantation). This type of treatment implies the collection of healthy blood stem cells from bone marrow, from umbilical cord blood or from circulating blood, and their transplantation into the patient. This can cure various blood diseases, such as leukemia, lymphomas or red blood cell disorders, bone marrow failure illnesses, some conditions that arise from abnormalities of immune cells or lack thereof and inherited metabolic diseases. As of recently (2024), another FDA approved stem cell therapy is “Rynocil”, a treatment based on mesenchymal stem cells (a subcategory of adult stem cells) that is aimed to treat steroid-refractory acute graft vs host disease (SR-aGVHD). This disease occurs after a hematopoietic cell transplant, if the transplanted cells attack the body of the recipient and the frontline method of treatment (high-dose corticosteroids) has proven ineffective. “Rynocil” virtually serves as a second-line treatment option, in hopes of prolonging the lives of patients with SR-aGVHD. Moreover, the FDA approves the types of stem cell therapies that are “autologous (derived from the patient being treated), minimally manipulated to maintain cell and tissue microarchitecture, and are intended for homologous use (FDA Section 361)” ¹¹, such as the “Adipose Tissue Graft procedure” to treat conditions of the knee, hip, shoulder and so on.

However, there are other stem cell therapies approved, for instance, by the EMA, like the usage of eye stem cells to restore sight after corneal injuries, known as “Holoclar” (limbal stem cell autograft transplantation). The limbus (area between cornea and conjunctiva) of patients who have suffered eye burns has been damaged, meaning that their limbal cells no longer work in corneal cell renewal, which further leads to the cornea becoming opaque, therefore to the loss of sight. This therapy works by extracting a portion of the patient’s own limbal cells, expanding them outside of the body (ex vivo), and then forming the actual “Holoclar” out of them, which is virtually a sheet of corneal epithelial cells with the purpose of regenerating and repairing the damaged cornea. In most cases, this therapy is to be used for the treatment of a single eye, and patients must have gone through a conjunctival limbal autograft treatment (a more traditional form of treatment, which involves extracting tissue from a healthy eye) in order to qualify for this procedure. Another example would be certain drugs like “Zemcelpro” (expanded and unexpanded umbilical cord cells), which are granted limited authorisation to treat adults with blood cancers, who have already undergone chemotherapy or radiotherapy (with the aim to destroy the diseased cells) and who have not been able to find a compatible hematopoietic stem cells donor. This medication has been tested in clinical trials and has shown some efficacy in neutrophil and platelet engraftment (the received stem cells established in the bone marrow of the recipient and started proliferating and producing the cell types mentioned), but it also poses a risk for various side-effects, like infections and acute or chronic graft-versus-host disease (the donor cells attack the body of the recipient).

On the other hand, there are plenty of experimental stem cell therapies that might have the potential to become official at some point in time. Also called investigational, these are the stem cell therapies that are still being tested in clinical trials and that have not yet been proclaimed as efficient and safe by a regulatory body. In order for a stem cell treatment to become official and appropriate for use in medical routine, it has to undergo highly-controlled clinical trials, rigorous analysis for scientific merit, and approval by an ethics committee; these steps often take several years to be completed, and it is not seldom the case that therapies subjected to clinical trials fail to achieve efficacy. The numerous experimental treatments are divided into several targeted diseases: neurodegenerative diseases (Parkinson’s disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), spinal cord injury), conditions of the eye, diabetes, diseases of the mouth (pulpitis, periodontitis, mandibular bony defects), heart conditions (heart attack, chronic heart failure) etc.

Advancements in research and treatment options (Romania, Germany, South Korea)

In the case of Romania, research advancements involve the conducting of various clinical trials in hopes to tackle diseases using stem cell therapies. One such clinical trial is testing the efficacy of mesenchymal stem cells (the ones derived from bone marrow or adipose/fatty tissue) in treating acute myocardial infarction, more commonly known as a heart attack (the death of heart muscles caused by insufficient blood flow to the heart, most commonly caused by a blockage of the coronary artery; if the problem is not fixed in time, it may lead to irreversible damage or death). Specifically, this trial’s aim is to determine how useful these cells are in improving the function of a heart after a patient has already suffered a heart attack, as they are able to differentiate, among others, into cardiomyocytes (the cells that form the heart’s muscles). Another trial is assessing how efficient stem cells are in treating congestive heart failure (the heart fails to pump enough blood in relation to the body, leading to blood build-ups in other areas of the body and even to blood clots, which may cause complications). This trial also has the purpose to achieve some sort of improvement in heart function, using the stem cells to regenerate and replace the damaged tissue. Apart from cardiomyocytes, MSCs can also specialise into endothelial cells, found in the lining of blood vessels, and smooth muscle cells, responsible in blood flow regulation. This ability of MSCs, alongside their secretion of growth factors, that promote angiogenesis (the formation of new blood vessels) and cytokines, which can stimulate tissue repair, give them impressive potential in tackling these usually life-altering heart conditions. Moreover, the discovery of induced pluripotent stem cells broadens the area of stem cell research in order to provide therapies for heart conditions, by culturing induced pluripotent stem cells and directing them to differentiate into the cells needed for the restoration and improvement of heart function.

Another clinical trial in Romania, that started somewhere around 2023, involved cord blood stem cells infusions as a potential treatment for autism in children. This trial was conducted by Dr. Felician Stăncioiu in Bucharest and was open to children with autism from all over the world, as long as they had previously had their own cord blood preserved at birth. The results of this trial focused on the experiences of two Romanian boys, Gabriel and Alex, who received both nutritional supplements and one stem cells intravenous infusion. As mentioned before, stem cell therapies usually require the use of immunity suppressing medication to prevent rejection, as was also the case for these children. In some cases, sedatives might have been used prior to the infusion, but the parents accompanying their children were usually successful in keeping them calm without the need for sedation. Both Alex and Gabriel showed improvement after the treatment. In a televised interview, Gabriel’s father stated that, since the infusion, his son’s temperament has ameliorated, his communication skills and interactions with his younger siblings getting better gradually. His hyperactivity also seemed to decrease after the treatment. In the case of Alex, his mother states in an interview that the infusion showed immediate results, curing his echolalia (the ability to only repeat what other people say, without producing one’s own speech). However, she is aware that this treatment is by no means a cure for autism, and that only through the other therapies that Alex was involved in, along with the parents’ efforts and the cord blood transplant, was the child able to catch up much faster with his cognitive, social and language delays.

Regarding stem cell treatment options in Romania, these mainly include the widely approved and recognized hematopoietic stem cell transplant, which has been described earlier in the article, and the participation in clinical trials, such as the ones mentioned above. Although some clinical trials prove to be effective for some people, all patients who choose to enroll must be aware of the risks and implications of such studies, which may consist of adverse effects or the inefficiency of the therapy. In addition, the haploidentical bone marrow stem cell transplant is available in Romania, being a crucial alternative for patients with blood diseases who have not been able to find fully compatible donors. Compassionate use (unapproved treatments being made available to patients whose diseases are rare or incurable, or who have no other options) is also allowed under certain circumstances. Other stem cell therapies available in Romania include “Rigenera”, a procedure that implies the transplant of progenitor cells                       (semi-differentiated stem cells), in order to treat conditions like arthrosis, burns, necrosis and scars, and certain therapies offered by some private clinics, but that are not necessarily approved or proven highly effective yet, such as treatments for neurodegenerative conditions, autism, arthritis, arthrosis, and autoimmune disorders, which are still in their clinical trial phases.

When it comes to Germany, extensive research and numerous clinical trials are done with the aim to find safe and efficient stem cell therapies for many different diseases. For instance, the German company “Bayer”, along with the American firm “BlueRock” have been leading clinical trials in hopes of securing a treatment for Parkinson’s disease (PD), which is the neurodegenerative disease with the second highest incidence, after Alzheimer’s. PD occurs because of the loss of midbrain dopaminergic neurons (the neurons that produce and release dopamine as their neurotransmitter) at a fast pace. As of today, the only therapies that ameliorate the motor issues of patients with PD are meant to increase the quantity of dopamine in the brain through drugs that mimic the role of naturally occurring dopamine, or to decrease levodopa (“the precursor to dopamine” ¹²) degradation. These methods do not actually tackle the very cause of PD, that is, the loss of dopamine-releasing neurons, and only have some benefits towards the motor function of the patients. Therefore, a new therapy has been going through its developmental stages, that being a dopaminergic neurons transplant into the putamen (“part of the basal ganglia on each side of the brain that help control movement and emotion” ¹³). Moreover, clinical trials regarding PD are also testing “bemdaneprocel”, a cell therapy involving allogeneic (cells that come from a different person than the recipient) human embryonic stem cells, which were used to obtain dopaminergic progenitor cells.

There are also other clinical trials in Germany which have shown some improvements in the patients’ conditions. For instance, stem cell therapies for blood diseases like sickle cell anemia, thalassemia (when the body does not produce enough hemoglobin, or lacks it completely – hemoglobin is the protein that binds to oxygen, and it is crucial in gas transportation around the body) and aplastic anemia (occurs when the bone marrow does not produce enough blood cells). There is also research going into cell therapies for cardiovascular diseases (which work through the mechanism described previously, in the section about Romania), autoimmune diseases, like multiple sclerosis (a disease where the myelin sheath of neurons is destroyed; it is also classified as a neurodegenerative disease), lupus (one’s own immune system attacks the body’s healthy tissues and organs, resulting in inflammation and discomfort) and rheumatoid arthritis (similar to lupus, but the immune system mainly damages the joints, along with other organs like the skin and eyes), liver diseases, such as cirrhosis (scarring of the liver tissue) and hepatitis (inflammation of the liver, most commonly caused by viral infections), and diabetes (the body produces little insulin or fails to do so completely, because the insulin-producing cells are destroyed by the immune system – type I, or it either gains resistance to the insulin produced or presents insulin hyposecretion – type II; both types have to do with pancreatic beta cells). As for now, the most efficient treatment for multiple sclerosis is represented by immunoablative therapy, which means that the immune system is first destroyed through a high dose of immunosuppressants, and it is then regenerated through hematopoietic stem cells infusion. However, this therapy is not necessarily safe, as it can lead to complications like infertility and neurological disabilities, and the only new ways of treating MS are in their early stages of investigation and involve the idea of regenerating damaged neurons using iPSCs (induced pluripotent stem cells). Regarding diabetes, the therapy being investigated aims to replace the destroyed (type I) or dysfunctional beta cells (type II) using pluripotent stem cells.

As treatment options for patients, apart from the clinical trials mentioned above, in which they can enroll while also considering all the possible risks, Germany offers, just like Romania, the hematopoietic stem cell transplant, which treats cancers like leukemia and lymphoma. Patients may also have access to treatments through compassionate use, but under strict regulations. Germany also has highly regulated private regenerative medicine clinics, such as “Anova IRM”, which works with treatments derived from autologous (they come from the patient themselves) adult mesenchymal stem cells, which target diseases like osteoarthritis, strokes, knee injuries, ALS, along with some of the ones discussed previously, like MS, PD, and rheumatoid arthritis. It is worth mentioning that none of these treatments will certainly cure said conditions, and the clinic in question clearly states this fact.

Regarding South Korea, it is important to mention that access to cell therapies that have not yet been granted market approval is legally allowed to patients with “severe, rare, or incurable” ¹⁴ diseases, according to a law which was enforced in February of 2025 (“Act on the Safety of and Support for Advanced Regenerative Medicine and Advanced Biological Products” ¹⁵). This means that even patients who do not participate in clinical trials have the chance to be treated with experimental stem cell therapies, as long as they are eligible for it (either there is no officially approved treatment for their disease, or their condition is “severe, rare, or incurable” ¹⁶, as stated above). This pathway is known as compassionate use. An important observation is that, in contrast with most countries,  in South Korea, treatments that involve minimally altered cells (such as injections with umbilical cord blood cells) are not included in the new “Regenerative Medicine Law” ¹⁷, therefore they are not offered by compassionate use programs. These types of treatments are regulated by the “Cord Blood Law” and are not in accordance with the new “Regenerative Medicine Law” ¹⁸.

One of the most recent advancements in cell therapy in South Korea is represented by what the participating companies claim will be the “first clinical-stage autologous induced pluripotent stem cell-derived therapy for peripheral artery disease and coronary artery disease” ¹⁹. This study is conducted by the firm “Cellino”, which specializes in biotechnology for regenerative medicine, in collaboration with “Karis Bio”, a South Korean company working on cell therapy. The treatment in question involves patient-derived iPSCs for angiogenesis in organs that are ischemic (they do not receive enough blood flow), which could be an alternative to the patients who may wish to avoid invasive procedures, such as bypass surgery (a procedure that makes a new path for blood to avoid, or to “bypass” a partially or fully blocked heart artery; it uses healthy vessels from the chest or leg, which is then connected to the heart and placed below the affected artery), while also ensuring compatibility with the people affected by the disease, since the stem cells come from the patients themselves. This therapy is already being tested in early phases clinical studies in South Korea.

Another significant advancement has been brought by “S.BIOMEDICS”, a South Korean company which has initiated a clinical trial for their “TED-A9” ²⁰ treatment, which is “high-purity ventral midbrain dopaminergic progenitor cells” ²¹, which have been obtained from human embryonic stem cells, while also ensuring Good Manufacturing Practice conditions. TED-A9 targets Parkinson’s disease, and the phase I/II clinical trial had 12 patients, 6 of which showed cell survival and engraftment after about one year from their treatment. All the patients had the specific cells transplanted in 3 sections of their putamen (anterior, middle, and posterior). These patients have shown, in different proportions, enhancements in their behavioral, motor, and non-motor symptoms caused by PD, none have shown complications related to their transplants, and no neurological or other side effects were experienced.

Moreover, South Korea has declared its wish to become a leader in stem cell research and cell therapy development, the government willing to invest over 400 billion won into 12 different branches of biotechnology, regenerative medicine being one of them. This initiative aims to help the industry shift to a more digital approach, offering funding for the integration of technology and artificial intelligence in this sector. Additionally, the government has planned to build “five national bio hubs by 2028” ²², equipped with state-of-the-art facilities, such as bio foundries (automated biological research facilities).

As for the treatment options available, apart from the ongoing clinical trials and the treatments available through compassionate use, government-certified clinics in South Korea, like “Medicell Plus”, offer therapy options for conditions like osteoarthritis (the cartilage at the extremities of the bones wears out in time, causing damage to joints), tendonitis (tendon inflammation), neurological and neurovascular diseases (mini strokes, caused by temporary blood clots, would be an example of a neurovascular disease). In addition, as with the other countries mentioned in the study, the hematopoietic stem cell transplant is standardised in South Korea, with the first of its kind in the country being performed in 1983 and its quality increasing over the years; nowadays, both allogeneic and autologous hematopoietic stem cell transplants are offered by South Korean hospitals, mainly targeting acute leukemia, lymphoma, myeloma (cancer that affects white blood cells), and aplastic anemia. Additional approved stem cell treatments in South Korea include: “Cardistem” – MSCs derived from cord blood cells, used for knee osteoarthritis; “Hearticellgram” – stem cells obtained from the bone marrow of the patient, aimed at the recovery of a heart after a myocardial infarction; “Queencell” – stem cells derived from the adipose layer of the patient, targeting perianal fistulas (abnormal tube-like structure that connects the anal canal to the skin surrounding the anus) caused by Crohn’s disease (a type of inflammatory bowel disease, which affects different parts of the digestive tract, depending on the patient).

Conclusions

Stem cells are miraculous organisms with the intriguing ability to differentiate into many types of cells that make up the human organisms. The main types of stem cells are embryonic stem cells (ESCs), which are pluripotent and can specialise into almost all the cells of the human body (apart from the cells that make up the placenta), adult/somatic stem cells, which are multipotent and can differentiate into a limited number of different cells, depending on which tissue they are found in (such as bone marrow cells, which can specialise into the various kinds of blood cells), and induced pluripotent stem cells (iPSCs), which are virtually adult stem cells that have been genetically reprogrammed to act like embryonic stem cells. Out of these three types, ESCs are the most controversial, as they can only be obtained through processes that ultimately destroy human embryos, and the ethical debate surrounding these cells has its base in the general view of the embryo, which stretches along a wide spectrum. In contrast, adult stem cells and iPSCs do not pose moral controversies, as they come from fully developed human tissues. Stem cells’ versatility makes them great candidates for research in regenerative medicine, holding the potential to repair and regenerate various damaged tissues, therefore possibly representing the cure for many diseases (neurodegenerative and cardiovascular diseases, diabetes, autoimmune conditions etc.). There are also already approved stem cells therapies, the most widely recognized one being the hematopoietic stem cell transplant, which has successfully treated blood diseases like leukemia and lymphoma.

In recent decades, humanity has witnessed remarkable progress in stem cell research. Experts have managed to find ways to isolate, culture and manipulate embryonic, adult, and induced pluripotent stem cells (the most recent type of stem cells, discovered in humans in 2007). These findings, along with deeper research and clinical trials which assess the safety and efficacy of stem cell therapies, could ultimately lead to cures for conditions we would have never thought of as treatable a few decades ago. Moreover, stem cells are important in many other fields, such as drug development and the study of disease mechanism, which makes them highly valuable research materials worldwide.

The comparative analysis between Romania, Germany, and South Korea underlines both the common features and the key differences found in the countries’ approaches to stem cell research, public attitudes, and treatment options. All three have achieved significant improvements in the field and are actively involved in advancing the field of regenerative medicine, attempting to make it safe and accessible.

Romania’s journey in cell biology research began in 1970, with the idea for the first Romanian center specialized in cell biology and pathology, the Institute of Cellular Biology and Pathology (ICBP) “Nicolae Simionescu”. Stem cell research started gaining attention in 2007, after Romania’s attendance at an international symposium discussing the subject, and, since then, the country has reached remarkable milestones, such as its first haploidentical stem cell transplant from 2015 and its clinical trials focusing on heart disease (myocardial infarct and congestive heart failure) and autism. Physicians have expressed their views on stem cell research and treatment through surveys, generally supporting the use of adult stem cells and cord blood banking at birth, but most showing disagreement towards research conducted on embryos, as many find it morally unacceptable.

Germany has marked the coinage of the term “stem cells” as we know it today, thanks to the zoologist Ernst Haeckel, and has shown very early scientific advancements, especially with its first successful blood stem cell transplant from 1985. However, its strict regulations, mainly the ones touching upon embryonic stem cells, have enforced limitations on extensive studies of this field. Since 2002, the laws became more permissive towards research on ESCs, permitting the country to become a forefront in the sector and to initiate clinical trials that focus on diseases such as Parkinson’s, multiple sclerosis, and diabetes. The public opinion in the country is overall supportive of regenerative medicine, with many people believing in the progression of the field, while putting an emphasis on trust in experts and scientific institutions and on the ethical implications of the research.

South Korea experienced rapid evolution in the field of stem cell research at the beginning of the 21^st century, more specifically in the early 2000s, the landmarks being both national scandals (such as the Hwang Scandal from 2004) and impressive breakthroughs (like Hwang Mi-Soon’s successful multipotent stem cell transplant from the same year, which helped her recover from spinal cord injury). In the years that have passed since then, the country has enforced a more organized and strict set of regulations, but it has also implemented laws that expand the access to stem cell therapies, the most recent one being from 2025 and addressing the legal availability of compassionate use programs for patients who need treatment but who are not enrolled in clinical trials. The general view of the South Korean public towards stem cell research and regenerative medicine is optimistic, though the overall take on the matter has been shaped by past controversies and feuds, decreasing the citizens’ trust in scientific experts. South Korea’s government is determined to make the country become one of the world’s leaders in this sector, standing out with substantial funding towards the development of research. Moreover, companies are organising clinical trials and actively researching new therapies, placing the accent on neurological and cardiovascular conditions.

 All in all, the approaches on stem cell research and regenerative medicine of Romania, Germany, and South Korea share common grounds, while also showing significant historical, cultural, and regulatory differences. All three perspectives are valid and emphasise the impressive potential of growth in this field on a global scale. The future is never set in stone, but only with passionate research, ethical sensibility, and international collaboration will we be able to fully unveil the wonders of stem cell therapies.

References (foot notes)

 

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