In this blog post, we will examine the basic principles of embryonic stem cells and the clinical and technical challenges involved in the laboratory cloning process, and explore how induced pluripotent stem cells and transdifferentiation technology might serve as alternatives.
What are stem cells?
Dr. Hwang Woo-suk’s stem cell research, published in ‘Science’ in the past, sparked a stem cell craze in South Korea. At the time, news outlets and newspapers intensively covered topics such as “what stem cells are” and “how they might be used in the future to benefit humanity.” However, subsequent stem cell-related papers by Dr. Hwang’s research team were retracted after it was confirmed that the research results had been fabricated. In particular, it was revealed that the key claim—that embryonic stem cells had been derived from human embryos cloned via somatic cell nuclear transfer—could not be substantiated. Today, stem cell research continues to attract significant attention, just as it did in the past; however, the focus has shifted from the development of a vague “panacea” toward understanding the principles of cell differentiation and regeneration, as well as developing cell therapies and disease models for treating intractable diseases such as Parkinson’s disease. Currently, pluripotent stem cells, including embryonic stem cells, are being utilized in various clinical studies and drug development; however, they are not yet established as a treatment for all intractable diseases.
Before delving into the discussion on the laboratory cloning of embryonic stem cells, let’s first examine the basic concepts of stem cells. Stem cells are cells that have not yet fully differentiated into specific cell types and possess the ability to proliferate and differentiate into various types of cells. Stem cells can be classified into several types based on their developmental stage and differentiation capacity; the most representative examples include embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Embryonic stem cells originate from the inner cell mass (ICM) located inside the blastocyst stage of an early embryo. When a fertilized egg undergoes cell division and reaches the blastocyst stage, cells that will develop into the embryo itself gather inside; these cells possess pluripotency, meaning they can differentiate into various cell lineages, including the ectoderm, mesoderm, and endoderm. Therefore, embryonic stem cells are pluripotent stem cells capable of differentiating into nearly all human somatic cell lineages. This differs from simply referring to the “endoderm” itself as embryonic stem cells, as explained in the original text. Embryonic stem cells originate from the inner cell mass of the blastocyst, and even within the inner cell mass, various cell lineages are distinguished depending on the stage of development.
Stem cells that do not require the direct use of embryos include adult stem cells and induced pluripotent stem cells. Adult stem cells are found in the tissues and organs of adults and play a role in maintaining and regenerating damaged tissue. Most adult stem cells possess multipotency—the ability to differentiate into cells of specific tissues or lineages—rather than the pluripotency of embryonic stem cells, which can differentiate into all cell types. For example, skin stem cells are involved in the regeneration of skin tissue, and hematopoietic stem cells in the bone marrow produce blood cells such as red blood cells, white blood cells, and platelets. Stem cells that maintain their respective tissues also exist in the intestinal epithelium and muscles. Hematopoietic stem cells are also present in umbilical cord blood, and these cells have long been used in the treatment of blood disorders. Finally, induced pluripotent stem cells (iPSCs) are not simply adult stem cells that have undergone genetic manipulation; rather, they are adult somatic cells—such as skin fibroblasts—into which specific factors have been introduced to reprogram them back to a pluripotent state. Because iPSCs possess pluripotency similar to that of embryonic stem cells, they enable research into differentiating them into various cell types without the direct use of embryos.
Why are embryonic stem cells clinically risky?
Currently, scientific and ethical debates are ongoing regarding research using embryonic stem cells and laboratory cloning. Proponents argue that harnessing the pluripotency of embryonic stem cells could lead to treatments for intractable diseases and the regeneration of damaged tissues, thereby significantly improving the quality of life for humanity. Opponents, on the other hand, contend that using embryos for research purposes raises issues regarding bioethics and human dignity. Furthermore, the laboratory cloning of embryonic stem cells must be evaluated not only for ethical concerns but also for scientific and clinical risks. In this article, we will examine the reasons for opposing the laboratory cloning of embryonic stem cells, focusing first on the clinical risks of embryonic stem cells, followed by the technical and ethical burdens arising during the experimental process, and finally, alternative stem cell and cell conversion technologies.
First, there are significant safety issues that must be resolved before embryonic stem cells can be used clinically. The pluripotency and high proliferative capacity of embryonic stem cells are significant advantages in various cell therapy studies. However, precisely because of these characteristics, if pluripotent cells that have not fully differentiated into the desired cell type remain in the body, there is a possibility that they could form tumors. In particular, because pluripotent stem cells can differentiate into various tissues, they can form teratomas—tumors consisting of a mixture of different tissue types—within the body. Rather than simply defining a teratoma as “a cancer cell with pluripotency,” it is more accurate to understand it as a tumor that may contain various tissues derived from the ectoderm, mesoderm, and endoderm. While teratoma formation is sometimes used as an experimental indicator to confirm pluripotency in stem cell research, the presence of undifferentiated pluripotent stem cells remaining in the body and forming teratomas during cell therapy poses a significant safety concern.
Consider a scenario in which neural cells are generated from embryonic stem cells and transplanted into a patient’s brain to treat a neurodegenerative disease such as Parkinson’s disease. In this case, it is crucial to ensure that the embryonic stem cells are sufficiently differentiated into the desired neural cell lineage and to verify that no undifferentiated cells or unwanted cells remain. If any undifferentiated pluripotent cells remain, they could proliferate within the body after transplantation or differentiate into various tissues, potentially forming tumors. Because of this risk, current stem cell-based cell therapy research places great emphasis on rigorously testing not only the identity of the cells but also their purity, safety, and the presence of any residual undifferentiated cells. In other words, the safety of clinical application is not guaranteed simply by the fact that embryonic stem cells have been differentiated into the desired cell type once.
In addition to the risk of teratomas, immune responses must also be considered in cell therapies using embryonic stem cells. An immune response refers to the reaction in which the immune system distinguishes cells or substances that have entered the body from its own tissues, recognizes them as foreign, and attacks them. Since typical embryonic stem cells can be derived from cell lines that are not genetically identical to the patient, there is a possibility that the transplanted cells will be attacked by the immune system. To mitigate this problem, methods such as considering human leukocyte antigens (HLA) or using immunosuppressive therapy are currently being researched. However, nuclear-transplanted embryonic stem cells—created by transplanting the patient’s somatic cell nucleus into an egg—can be engineered to match the patient’s nuclear DNA, potentially offering an immunological advantage over conventional embryonic stem cells. Nevertheless, even in this case, the mitochondrial DNA derived from the egg may differ from that of the patient, so it cannot be concluded that the immune response will be completely eliminated. Therefore, rather than simplifying the matter by stating that “the patient is 50% genetically identical or completely different,” it is more accurate to understand that immunological characteristics vary depending on differences in cell origin, nuclear DNA, mitochondrial DNA, and HLA.
Since the use of immunosuppressants to suppress immune responses can increase the risk of infection or other complications, this burden must also be considered in long-term treatment. Of course, not all embryonic stem cell-based therapies require the same degree of immunosuppression; this varies depending on the cell type, the patient’s immunological characteristics, the transplant site, and HLA compatibility. Ultimately, to use embryonic stem cells in actual patients, multiple stages of validation are necessary—not only the technology to precisely differentiate them into the desired cell types but also measures to reduce the potential for tumor formation, regulate the immune response after transplantation, and confirm long-term safety and efficacy. Thus, while the pluripotency of embryonic stem cells is a major advantage, it must also be recognized that, in a clinical setting, this very pluripotency and proliferative capacity can lead to safety concerns.
Why are success rates and egg procurement problematic?
Furthermore, the laboratory production of embryonic stem cells faces challenges related to technical efficiency and the procurement of oocytes. In particular, when creating embryonic stem cells using somatic cell nuclear transfer (SCNT), the process does not involve using fertilized eggs directly. Instead, the nucleus is removed from an oocyte, the nucleus of a somatic cell from a patient or research subject is transferred into it, embryonic development is induced, and stem cells are harvested at the blastocyst stage. In the past, the success rate of this process was very low, leading to the belief that a large number of oocytes were required; the original text also cites a figure stating that approximately 200 fertilized eggs are needed to obtain a single embryonic stem cell. However, this figure cannot be used as a general benchmark representative of the current technological level. As research methods have improved, it has been reported that in certain experiments using high-quality oocytes, somatic cell nuclear-transplanted embryonic stem cell lines can be established with a much smaller number of oocytes. Therefore, rather than generalizing the current success rate based on a single figure like “1 in 200,” it is more appropriate to emphasize that the development of somatic cell nuclear transfer embryos and the efficiency of stem cell line establishment vary significantly depending on various factors—such as egg quality, activation methods, and culture conditions—and that this remains a technically challenging process.
Above all, the fact that this process requires oocytes is a critical issue. While sperm can be obtained relatively easily, oocytes must be retrieved directly from a woman’s ovaries, and it is difficult to secure a sufficient number for research through natural ovulation alone. Therefore, ovulation induction and hyperovulation induction procedures may be used to obtain multiple oocytes. Although superovulation is a widely used method in reproductive medicine, side effects such as ovarian hyperstimulation syndrome (OHSS) can occur during the process of using hormones to induce the simultaneous growth of multiple follicles. While symptoms are usually mild, severe cases may involve ascites and shortness of breath, potentially requiring hospitalization. Consequently, the process of securing eggs for research cannot be viewed merely as a matter of obtaining materials for the laboratory; it must also take into account the physical burden and safety of the egg donors, as well as adequate informed consent, voluntary participation, and appropriate research ethics and oversight.
Therefore, it is not possible to simply calculate that a certain number of eggs will inevitably yield a single embryonic stem cell, as has been suggested in the past. This is because the condition of each egg varies, and the development of somatic cell nuclear transfer embryos and the establishment of stem cell lines depend on experimental conditions. Nevertheless, unlike methods that use other types of cells, somatic cell nuclear transfer necessarily requires human eggs, leaving the fundamental issue that the egg retrieval process may impose a medical burden on women. International stem cell research guidelines also place significant emphasis on procedures related to the donation of oocytes for research purposes, addressing the physical burden and safety of oocyte donors, the need for voluntary and informed consent, and measures to prevent undue inducement or exploitation. Therefore, when evaluating the efficiency of embryonic stem cell laboratory cloning, one must consider not only the simple success rate of the experiments but also the biological and ethical costs incurred during the process of obtaining oocytes.
How might induced pluripotent stem cells and transdifferentiation serve as alternatives?
Finally, there are stem cells and new cell reprogramming technologies that can replace embryonic stem cells. Induced pluripotent stem cells, mentioned earlier, are a prime example, and transdifferentiation—or direct cell reprogramming—is also being researched as an important alternative. Induced pluripotent stem cells (iPSCs) are created by introducing specific transcription factors into somatic cells—such as a patient’s skin fibroblasts—to reset the cell’s differentiation state and restore its pluripotency. Therefore, they offer the advantage of producing cells with pluripotency similar to that of embryonic stem cells without the direct use of embryos. In particular, when iPSCs are derived from the patient’s own cells, there is a possibility of producing cells that are a perfect match for the patient, which can be immunologically advantageous. However, it cannot be definitively stated that “there is absolutely no immune rejection.” This is because, even with autologous cells, an immune response may occur depending on genetic and epigenetic changes that arise during the reprogramming process or on the characteristics of the differentiated cells. Therefore, iPSCs also require verification of safety and immunogenicity before they can be applied clinically.
Another advantage of iPSCs is that they do not require the direct use of oocytes. Since they are created by reprogramming the patient’s somatic cells, the process of obtaining somatic cells is relatively simpler than that of oocyte retrieval. Furthermore, because iPSCs can be proliferated in large quantities and then differentiated into the desired cell types, they are being utilized in various fields, such as the creation of disease models, drug development, and cell therapy research. However, iPSC technology is not yet fully mature. Challenges remain, including genetic and epigenetic changes that may occur during reprogramming, the risk of tumor formation due to residual undifferentiated cells, and difficulties in fully maturing the cells into the desired cell types. Therefore, rather than simply comparing embryonic stem cells and induced pluripotent stem cells as if one were a perfect technology, we must assess their respective advantages and risks to determine their potential for clinical application.
In the case of transdifferentiation, instead of first reverting somatic cells to a pluripotent state and then differentiating them into the desired cell type, a single somatic cell is directly converted into a different type of cell. For example, this involves directly converting skin fibroblasts into desired cells, such as neurons, using specific transcription factors or other reprogramming methods. While induced pluripotent stem cells follow the process “somatic cell → pluripotent induced pluripotent stem cell → cells of the desired tissue or organ,” transdifferentiation aims for the direct pathway “somatic cell → desired cell.” Since this process does not involve a pluripotent state, it has the advantage of reducing the risk of tumor formation caused by the residual presence of undifferentiated pluripotent cells. However, transdifferentiation is not a technology that has resolved all issues. Cell conversion efficiency may be low, or the generated cells may not mature sufficiently; furthermore, challenges remain in ensuring the function and long-term stability of the target cells. Therefore, it is more accurate to view transdifferentiation not as a fully developed therapeutic technology that has already eliminated all risks associated with embryonic stem cells, but rather as a promising research method for directly generating target cells without passing through the pluripotent state.
How should the direction of embryonic stem cell research be set?
The pluripotency of embryonic stem cells offers significant potential for researching various intractable diseases facing humanity and developing new treatments. However, this potential alone does not guarantee safety in clinical applications. In cell therapy using embryonic stem cells, we must consider the possibility of undifferentiated cells forming tumors, the difficulty of accurately differentiating them into the desired cell types, immune responses following transplantation, and the physical and ethical burdens associated with obtaining the oocytes required for somatic cell nuclear transfer. Furthermore, current research shows that various alternatives—including induced pluripotent stem cells (iPSCs) and direct cell reprogramming technologies—are rapidly advancing alongside embryonic stem cells. Therefore, rather than viewing the laboratory replication of embryonic stem cells as the sole path to treating intractable diseases, it is necessary to advance research by comparing the safety, efficacy, and ethical burdens of various approaches, including iPSCs and transdifferentiation technologies that do not use embryos. In particular, since iPSCs and transdifferentiation also have their own limitations, it is important to rigorously verify whether they can meet the safety and efficacy requirements of actual clinical practice, rather than treating any single technology as an unconditional substitute. If research progresses in this direction, we will be able to fully understand the scientific potential of embryonic stem cells while reducing the burdens associated with human life and safety and securing a wider range of options for treating intractable diseases.
