In this blog post, we will look at how stem cell technology is used in regenerative medicine and the ethical and scientific issues that arise from this.
Recently, the National Geographic Channel covered regenerative medicine, and the most popular technology in regenerative medicine is stem cell technology. Stem cells are used to “cultivate” organs directly in the laboratory, creating organs that do not cause rejection and transplanting them into patients. This article will explain stem cells, which are in the spotlight in many fields of biochemistry and medicine.
Stem cells are “undifferentiated cells that can develop into any tissue,” and are also known as pluripotent cells. “Undifferentiated cells” are cells that have not yet been determined to become any specific cell or tissue, and are in the state of undifferentiated cells during the blastocyst stage, when the embryo is created by the division of a fertilized egg in the uterus. The process of undifferentiated cells becoming cells with specific functions, such as nerve cells, muscle cells, and skin cells, is called “differentiation.” The type of cell that a cell will differentiate into is determined by which of the various types of transcription factors in the egg enter the cell as the fertilized egg divides. For example, if there is a transcription factor that attaches to the transcription regulatory element of the transcription initiation complex that expresses the genes essential for skin cells, the undifferentiated cells will differentiate into skin cells. Stem cell technology uses this property of undifferentiated cells to make them differentiate into the cells or tissues that the experimenter wants. There are three main types of stem cells: embryonic stem cells, adult stem cells, and reprogrammed stem cells.
Embryonic stem cells can be divided into two types, depending on the method of cell extraction: fertilized embryo stem cells and nuclear-transferred embryo stem cells. Fertilized embryo stem cells are cells isolated from the inner cell mass of blastocysts of fertilized embryos. Since they have not yet differentiated, they have the “pluripotency” to differentiate into all cells and tissues. There are two types of blastomeres: outer and inner. Only the inner blastomeres develop into a blastula, so instead of using fertilized eggs that contain genetic information other than information about the blastula, the inner blastomeres are used as stem cells. The research on these cells began in 1998 when the Thompson and Gearhart research team in the United States first isolated human embryonic stem cells. There are several problems with this method. First, if differentiation occurs through this blastocyst state, an individual is born who is a perfect human being. In other words, it raises the issue of the trivialization of life, where parts of a child’s body are removed before the baby is born and used for others. In fact, after some of the cells in the blastocyst are removed, the baby is destroyed without being born. In other words, a life is destroyed to obtain stem cells. In addition, since the cells used are genetically differentiated from the stem cells of another person, an immune rejection reaction may occur. And since this technology itself is very difficult, there is a risk that cancer cells may be created.
Nucleus-replacement embryonic stem cells use an egg instead of a fertilized egg. First, the nucleus of the patient to be transplanted is extracted and then placed in the egg from which the nucleus has been removed. After the egg is developed into a blastocyst, the rest of the process is the same as that of fertilized embryonic stem cells. Dolly the sheep, born in 1997, used this nuclear replacement technology. Although Dolly did not use stem cells, she was born by developing the nucleus-replaced egg itself in another sheep’s womb. Nuclear replacement embryo stem cells are less likely to be considered a threat to life because they only use eggs, not fertilized eggs, but ethical issues can arise if there is a question as to whether eggs are also life. Although the cells have been genetically modified to have normal performance, the DNA in the cell organelles, such as mitochondria and chloroplasts, still exists in the egg cells, so there is a very small chance that an immune rejection reaction may occur. However, the technology itself is difficult, so the possibility of cancer cells still exists.
Adult stem cells are undifferentiated cells found among differentiated cells in tissues or organs, and are stem cells that remain in extremely small quantities even after becoming adults. Adult stem cells can be obtained from human skin, bone marrow, umbilical cord, etc. Unlike embryonic stem cells, they have multipotent properties rather than typical properties. In other words, stem cells obtained from the skin differentiate into skin cells, stem cells obtained from the bone marrow differentiate into blood cells (red blood cells, white blood cells, and platelets), and stem cells obtained from the umbilical cord differentiate only into the tendons of the umbilical cord. Adult stem cells have the longest history, with Till and McClough studying hematopoietic stem cells, one of the stem cells that can be obtained from bone marrow, in 1961. A typical example of adult stem cells is pluripotent hematopoietic stem cells, which migrate to damaged tissues when a certain tissue is damaged. Unlike embryonic stem cells, it does not use eggs or fertilized eggs, so there are no bioethical issues. However, it is very difficult to isolate because it is present in very small amounts in the body, and because it is pluripotent rather than totipotent, the range of use is very narrow. It cannot be donated to other patients due to immune rejection, and only the patient’s own adult stem cells can be used.
Ectopic differentiation stem cells are cells that have been differentiated and then re-differentiated into undifferentiated cells by introducing regulatory genes into fully differentiated cells, and are also called IPS cells or induced pluripotent stem cells. Here, the regulatory gene is a gene that encodes a regulatory protein that induces transcription in the transcription initiation complex. This technology was first successfully extracted from cells using a retrovirus and mice by a team from Yamanashi, Japan, in 2007, and for this achievement, they received the Nobel Prize in Physiology or Medicine. To create reprogrammed stem cells, it is necessary to inject reprogramming factors into the cells. Initially, retroviruses were used, but this led to the problem of viral genes being inserted together, so now, plasmids or proteins are used without the introduction of foreign genes. The most promising of the three types of stem cells, induced pluripotent stem cells (iPSCs) were initially expected to be able to regenerate human body parts, just as a lizard’s tail could be regenerated. This technology is currently the most hotly researched field in the field of regenerative medicine. The reason why these cells are in the spotlight is that they have the typical performance of embryonic stem cells, but without the concerns about the risk of life and immune rejection (assuming that the patient’s cells are re-differentiated) that are associated with adult stem cells. Just as the smartphone was created by combining the advantages of a computer and a telephone, embryonic stem cells and adult stem cells have been combined to create the advantages of both. The disadvantages are that it is very difficult to extract, that is, the efficiency of re-differentiation is very low, and that it is a cell that has been artificially created, unlike embryonic stem cells and adult stem cells, so its genetic stability is poor. However, these disadvantages are likely to be improved as research into regenerative medicine is currently being actively conducted. For example, Professor Oh Il-hwan’s team at Catholic University of Korea found that undifferentiated cells have loose chromatin, unlike differentiated cells, and are currently researching methods to loosen the chromatin. In addition, research has been conducted to increase the efficiency of reprogramming by 100 to 3,000 times by reprogramming neural stem cells, one of the adult stem cells, into neural stem cells.
The biggest problem with stem cells is the disregard for life. In order to create embryonic stem cells, a fertilized egg must be created by the union of a sperm and an egg. However, most people believe that the process of sperm and egg meeting is the process of creating a new and sacred life, a child. From this perspective, embryonic stem cell technology takes the life of a baby and is used to extend the life of a person who is currently alive through organ transplants. The situation is even more serious when it comes to legal and religious issues. In Korea, the use of embryos that can develop into a living being or donated eggs as stem cells is prohibited by the Bioethics and Safety Act, but the use of sperm and unfertilized eggs or frozen embryos that are scheduled to be discarded after infertility treatment as stem cells is permitted. The content of this law alone shows that there is much controversy over how far one should recognize a precious life.
Another major problem with stem cells is the immune rejection reaction. When foreign tissue enters the body, the immune system recognizes it as an antigen and attacks and eliminates it. For example, when blood of a different blood type enters the blood vessels, the original clotting factor reacts with the newly introduced clotting factor, causing the blood to clot. Heterologous embryonic stem cells, which have a different nucleus from the beginning, and allogeneic embryonic stem cells, which have a different nucleus in the cytoplasm, can cause a serious rejection reaction when transplanted. In other words, the immune system in the patient recognizes the transplanted organ as an external substance and attacks it. Adult stem cells and reprogrammed stem cells can also cause an immune rejection reaction when transplanted from another person.
The greatest use of stem cells is that they can repair damaged or destroyed tissues, which can be used to treat various incurable diseases. In 2003, a team led by Dr. Se-pil Park in South Korea differentiated human embryonic stem cells into dopamine-secreting neurons and treated mice with Parkinson’s disease, which is a degenerative brain disease and one of the incurable diseases. Dr. Hwang Woo-suk also used stem cells to treat dogs with spinal cord injuries. In addition, by creating insulin-producing beta cells, it is possible to treat type 1 diabetes, an incurable disease that causes a person to be dependent on insulin injections for life due to a congenital lack of beta cells. And according to the National Geographic Channel, which was mentioned at the very beginning, Luke Marsella’s bladder, which had congenital spina bifida, caused reflux and damaged his kidneys. Dr. Anthony Atala used bladder stem cells, a type of adult stem cell from Luke, to culture and implant a new bladder into Luke, and Luke is now free from the risk of organ damage.
Another use for stem cells is in infertility treatment. Not only human embryonic stem cells, but also stem cells made by reprogramming skin cells to make sperm or eggs, are used for in vitro fertilization. In 2014, Stanford University’s Dr. Rei Ho Perra reprogrammed the skin of a man with a Y-chromosome abnormality and then reprogrammed it into sperm. In addition, disease modeling is being conducted to reverse-differentiate diseased cells and understand the process of disease development, and cell research for the development of new drugs to prevent the process of genetic diseases is also being conducted. Research is also being conducted to identify genes involved in the development and differentiation of stem cells by creating stem cells and observing the process of cell differentiation. These examples show that there is a great potential for the use of stem cells, especially those that have been reprogrammed.
Another important aspect of stem cell research is its economic impact. If stem cell technology is commercialized, it will create many jobs and the related industries are likely to grow rapidly. For example, if a customized treatment using stem cells is developed, it will be more effective than existing drug treatments and will contribute to reducing medical expenses. In addition, stem cell research in the field of biotechnology will lead to the development of new drugs and the advancement of regenerative medicine, and will bring about major changes throughout the medical industry. These technological advances will have a positive impact on the national economy and will also play an important role in strengthening competitiveness in the global market.
We have learned about stem cells so far. Stem cells are cells with typical properties, and there are embryonic stem cells, adult stem cells, and reprogrammed stem cells. Each type of stem cell has its own advantages and disadvantages, but the most serious disadvantages are the issues of life-dismissal and immune rejection. However, if these issues are resolved, they have tremendous potential to be widely used in various fields, including medicine, cytology, and pharmacology. In addition, when you consider the economic potential of stem cell research, you can see how important research and development in this field is.
