How can stem cell technology be used in regenerative medicine, and what are the ethical issues and scientific challenges?

Stem cell technologies are utilized to repair damaged tissues and treat incurable diseases by leveraging their pluripotency to differentiate into various cells and tissues, and include embryonic stem cells, adult stem cells, and reverse differentiated stem cells. Each technology poses ethical and scientific challenges, such as disregard for life and immune rejection, but each has the potential to make significant contributions to regenerative medicine and the economy if addressed.

 

The National Geographic Channel recently covered regenerative medicine, and one of the most promising technologies is stem cell technology. Stem cells are used to “grow” organs directly in the laboratory to “create” organs that will not be rejected and transplanted into patients. In this article, we’ll explain what stem cells are, which are gaining attention in many biochemical and medical fields.
Stem cells are defined as “undifferentiated cells that can develop into any tissue” and are also called pluripotent cells. An undifferentiated cell is a cell that has not yet decided what kind of cell or tissue it will become. An embryo is an undifferentiated cell at the blastocyst stage when a fertilized egg divides in the womb. When an undifferentiated cell becomes a cell with a specific function, such as a nerve cell, muscle cell, or skin cell, it is called “differentiating.” What kind of cell it becomes is determined by the different transcription factors in the egg that enter the cell as it divides. For example, if a transcription factor is present that attaches to a transcriptional regulatory element of the transcription initiation complex that expresses a gene essential for skin cells, the undifferentiated cell will differentiate into a skin cell. Stem cell technology uses these properties 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 reverse differentiated stem cells.
Embryonic stem cells include fertilized embryonic stem cells and nuclear transferred embryonic stem cells, depending on how the cells are extracted. Fertilized embryonic stem cells are cells isolated from the inner cell mass of the blastocyst of a fertilized egg embryo and have the “pluripotency” to differentiate into all cells and tissues because they have not yet differentiated. The blastocyst contains an exocytoplasm and an endocytoplasm, but only the endocytoplasm develops into a blastocyst, so rather than using a fertilized egg that contains genetic information other than that of the blastocyst, the endocytoplasm is used as a stem cell. Research on these cells began in 1998, when Thompson and Gearhart’s team in the United States isolated the first human embryonic stem cells. There are a number of problems with this approach, the first of which is that the blastocyst, when it differentiates, creates a single, complete human being, which means that before the baby is born, parts of the child’s body are removed and used for the benefit of someone else, which is disrespectful of life. In fact, by removing some cells from the blastocyst, you are not creating a baby, you are destroying it, so you are destroying a life to get stem cells. Also, because you are using cells that are genetically differentiated from someone else’s stem cells, there is a risk of immune rejection. And because the technique itself is so difficult, there is a risk that cancer cells could be created.
Nuclear replacement embryonic stem cells use eggs instead of fertilized eggs. The process is the same as with fertilized embryonic stem cells: first, the patient”s nucleus is extracted, then the nucleus is placed in a de-nucleated egg, which then develops into a blastocyst. This is how Dolly, a cloned sheep born in 1997, was created using nuclear transfer technology. Dolly was born in 1997, using no stem cells, but the egg itself, which was fertilized in another sheep’s uterus. Although the use of embryonic stem cells is less disrespectful of life because it uses only eggs, not fertilized eggs, it can still raise ethical issues if one questions whether eggs are life. There is a very small chance of immune rejection because the DNA in the organelles such as mitochondria, chloroplasts, etc. is still present in the egg, even though it is fully functional and the nucleus has been implanted. However, due to the difficulty of the technique, there is still the possibility of cancer cells developing.
Adult stem cells are undifferentiated cells found among the differentiated cells of a tissue or organ, and they are the stem cells that remain in very small quantities after reaching adulthood. Adult stem cells can be obtained from human skin, bone marrow, or umbilical cord, and unlike embryonic stem cells, they are pluripotent rather than multipotent, meaning that stem cells from skin can differentiate into skin, stem cells from bone marrow can differentiate into blood cells (red blood cells, white blood cells, and platelets), and stem cells from umbilical cord can only differentiate into tendons of the umbilical cord. Adult stem cells are the oldest, with Till and McCloach describing hematopoietic stem cells, a type of stem cell that can be obtained from bone marrow, in 1961. A classic example of an adult stem cell is the pluripotent hematopoietic stem cell, which means that when one tissue is damaged, cells from other organs can be recruited to repair the damaged tissue. Unlike embryonic stem cells, no eggs or fertilized eggs are used, so there are no bioethical issues, but they are too difficult to isolate because there are very few of them in the body; the range of uses is too narrow because they are pluripotent rather than unipotent; they cannot be donated to other patients because of immune rejection; and they can only be used with your own adult stem cells.
Reverse-differentiated stem cells are cells in which a regulatory gene has been introduced into a fully differentiated cell, causing the cell to reverse differentiate into an undifferentiated cell, and are also called IPS cells or induced pluripotent stem cells. A regulatory gene here is a gene that encodes a regulatory protein that directs transcription at the transcription initiation complex. This technique was most recently developed in 2007 by Yamanaki’s team in Japan, who first succeeded in extracting the cells using retroviruses and mice, and were awarded the Nobel Prize in Physiology or Medicine for their work. Initially, viruses such as retroviruses were used to inject the reverse differentiation factor into the cells, but problems with the insertion of viral genes occurred, so plasmids or proteins that do not introduce foreign genes are currently used. Reverse differentiation stem cells are the most promising of the three, and when the technology was first announced, it was hoped that humans could regenerate body parts in the same way that a lizard can regrow its tail. This technology is currently the hottest area of research in regenerative medicine. What makes these cells so appealing is that they have the full range of capabilities of embryonic stem cells, and they don’t have to worry about the lifespan issues or immune rejection (assuming they are reverse-differentiated from the patient’s own cells) of adult stem cells. It’s like combining the best of computers and phones to create a smartphone, but with the best of both embryonic and adult stem cells. The disadvantages are that they are very difficult to extract, i.e., the efficiency of reverse differentiation is very low, and unlike embryonic stem cells and adult stem cells, they are not genetically stable because they are artificially created, but these disadvantages are likely to be improved because they are currently being actively researched in regenerative medicine. For example, a team led by Professor Oohwan Yoo at Catholic University found that undifferentiated cells have loose chromatin, unlike differentiated cells, and are currently researching ways to loosen chromatin. They have also been able to reverse differentiate neural stem cells, one of the adult stem cells, and increase the efficiency of reverse differentiation by about 100 to 3000 times.
The biggest problem with stem cells is their disregard for life. To create embryonic stem cells, a sperm and egg must meet to create a fertilized egg. However, most people think of the process of fertilization as the creation of a new, sacred life – a child. From this perspective, embryonic stem cell technology takes the life of a baby and uses it to prolong the life of a living person by transplanting organs. It is even more serious when it comes to legal and religious issues. In Korea, the Bioethics and Safety Act prohibits the use of embryos or donated eggs that can grow into living beings as stem cells, but it is allowed to use sperm and unfertilized eggs or frozen embryos that are scheduled to be discarded after fertility treatment as stem cells. The wording of this law alone suggests that there is a lot of debate about what constitutes a human life.
Another big problem with stem cells is immune rejection, which is when a tissue that is not your own enters the body, the immune system recognizes it as an antigen and attacks and eliminates it. A classic example is when blood of a different blood type enters the blood vessels, the original clotting factors react with the new ones, causing the blood to clot. Fertilized embryonic stem cells, which have different nuclei from the start, and nucleus-substituted embryonic stem cells, which have different nuclei in their cytoplasm, can result in severe rejection when transplanted, meaning that the patient’s own immune system recognizes the transplanted organ as foreign and attacks it. Adult stem cells and reverse differentiated stem cells can also cause immune rejection when transplanted from another person.
The greatest use of stem cells is their ability to repair damaged or destroyed tissue, which can lead to the treatment of many incurable diseases. In 2003, Dr. Se-Pil Park and colleagues in South Korea differentiated human embryonic stem cells into dopamine-secreting nerve cells to treat mice with Parkinson’s disease, a degenerative brain disorder and one of the most incurable diseases. Dr. Woo-Seok Hwang also used stem cells to treat dogs with spinal cord injuries. They can also create insulin-producing beta cells to treat type 1 diabetes, an incurable disease in which patients are born with a low number of beta cells and are dependent on insulin injections for life. And according to the National Geographic Channel, which we mentioned at the beginning, Luke Masella’s congenital spina bifida caused his bladder to reflux and damage his kidneys. Dr. Anthony Atala used Luke’s bladder stem cells, a type of adult stem cell, to grow a new bladder and transplant it into Luke, who is now at no risk of organ damage.
Another use of stem cells is to treat infertility. Human embryonic stem cells, as well as stem cells made by reverse differentiation of skin cells, are used to create sperm or eggs for in vitro fertilization. In 2014, Dr. Reijo Pera of Stanford University reverse-differentiated the skin of a man with azoospermia due to a Y-chromosome abnormality and then re-differentiated it into sperm. In addition, cell research is also being conducted for disease modeling, in which diseased cells are reverse-differentiated to understand the process of disease, and for drug development, in which the process of genetic disease is analyzed to prevent the process. Stem cell research is also being conducted to identify genes involved in development and differentiation by creating stem cells and observing how they differentiate. These examples show that stem cells, especially reverse differentiated stem cells, have a lot of potential applications.
Another important aspect of stem cell research is the economic impact. Once stem cell technology is commercialized, it will create a large number of jobs, and related industries will likely boom. For example, if personalized therapies are developed using stem cells, they could be more efficient than traditional drug treatments and contribute to reducing healthcare costs. In the field of biotechnology, stem cell research will also lead to the development of new drugs and advances in regenerative medicine, revolutionizing the healthcare industry as a whole. These technological advances will have a positive impact on national economies and will play an important role in enhancing competitiveness in the global market.
So far, we’ve learned about stem cells. Stem cells are cells that have the potential to become any of the following: embryonic stem cells, adult stem cells, and reverse differentiated stem cells. Each type of stem cell has its own advantages and disadvantages, the most serious of which are the problems of disrespect for life and immune rejection. However, once these issues are resolved, they have enormous potential for widespread use in medicine, cytology, pharmaceuticals, and other fields. Add in the economic potential of stem cell research, and you can see how important it is to continue researching and developing this field.